liu.seSearch for publications in DiVA
Endre søk
Begrens søket
123 51 - 100 of 117
RefereraExporteraLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Treff pr side
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Forfatter A-Ø
  • Forfatter Ø-A
  • Tittel A-Ø
  • Tittel Ø-A
  • Type publikasjon A-Ø
  • Type publikasjon Ø-A
  • Eldste først
  • Nyeste først
  • Skapad (Eldste først)
  • Skapad (Nyeste først)
  • Senast uppdaterad (Eldste først)
  • Senast uppdaterad (Nyeste først)
  • Disputationsdatum (tidligste først)
  • Disputationsdatum (siste først)
  • Standard (Relevans)
  • Forfatter A-Ø
  • Forfatter Ø-A
  • Tittel A-Ø
  • Tittel Ø-A
  • Type publikasjon A-Ø
  • Type publikasjon Ø-A
  • Eldste først
  • Nyeste først
  • Skapad (Eldste først)
  • Skapad (Nyeste først)
  • Senast uppdaterad (Eldste først)
  • Senast uppdaterad (Nyeste først)
  • Disputationsdatum (tidligste først)
  • Disputationsdatum (siste først)
Merk
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 51.
    Jönsson, Anna K.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Drug-related morbidity and mortality: Pharmacoepidemiological aspects2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Adverse drug reactions (ADRs) constitute a significant health problem with consequences for the patient as well as for society. Suspected ADRs have been reported to occur in about 2-14% of hospitalised patients. In about 5% of deceased hospitalised patients suspected ADRs may have caused or contributed to the fatal outcome. When a pharmaceutical drug is approved for marketing, the drug has been tested only on a limited number of patients (often <6000) for a limited time period in a controlled environment. Hence mostly common ADRs are detected in these trials. Moreover, certain patient groups, for example patients with co-morbidities, elderly patients, children and pregnant women are often not included in these studies. Thus, it is important to closely monitor the use of drugs after marketing to observe new effects and detect new ADRs.

    The aim of this thesis is to describe the pattern of pharmaceutical substance use related to morbidity and mortality and to investigate two serious ADRs. We have studied the incidence of fatal ADRs, fatal intoxications, cerebral haemorrhage related to warfarin treatment and venous thromboembolism (VTE) related to treatment with antipsychotic drugs.

    Observational studies form the basis for this thesis. Data from the Swedish Cause of Death Register, medical case records, the Swedish database on ADRs, the forensic pathology and forensic toxicology databases, and Swedish and Danish hospital discharge registers, Danish prescription registers, and civil registry systems were used.

    In Paper I we found that 3% of all fatalities in a Swedish population were related to a suspected ADR. Of the deceased hospitalised patients, 6% were related to a suspected ADR. Haemorrhage was the most commonly observed fatal suspected ADR, accounting for almost two-thirds of the events and anticoagulantia was the most common drug group associated with fatal suspected ADRs (almost 50%). A suspected intoxication could have contributed to the fatal outcome in 0.6% of the deceased. Among the fatal intoxications in Swedish medico-legal autopsies studied in Paper II, on average four substances were detected per case. The five most commonly detected substances in individuals with a fatal intoxication were ethanol, propoxyphene, paracetamol, diazepam and flunitrazepam. Among patients diagnosed with cerebral haemorrhage, 10% (59 cases) were treated with warfarin at onset of symptoms (Paper III). Of these, 7 cases (12%) were considered to have been possibly avoidable since the patients were treated with concomitant drugs that have the potential to enhance warfarin effects. The results from Paper IV and Paper V in combination with the published literature suggest that patients treated with antipsychotic drugs have an increased risk for VTE. Compared with non-users, an adjusted odds ratio for VTE of 2.0 was found for users of any antipsychotic drugs in a Danish population. In a medico-legal autopsy series, an adjusted odds ratio for fatal pulmonary embolism of 2.4 and 6.9 was found for users of first-generation low-potency antipsychotics and second-generation antipsychotics, respectively.

    In summary, drug-related morbidity and mortality is a significant problem and suspected ADRs contribute to a substantial number of deaths. Fatal intoxications are relatively common and it is important to observe changes in patterns of substances associated with fatal intoxications to be able to discover new trends and monitor effects of preventive work. A significant proportion of warfarin-related cerebral haemorrhage was caused by drug-drug interactions and was considered possible to avoid. Users of antipsychotic drugs may increase the risk of VTE.

    Delarbeid
    1. Incidence of fatal adverse drug reactions: A population based study
    Åpne denne publikasjonen i ny fane eller vindu >>Incidence of fatal adverse drug reactions: A population based study
    Vise andre…
    2008 (engelsk)Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, nr 4, s. 573-579Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    What is already known about this subject

    • Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.

    • The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.

    • In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.

    What this study adds

    • Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.

    • Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.

    • Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.

     

    Aims: To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.

     

    Methods: Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.

     

    Results: Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.

     

    Conclusions: The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

    sted, utgiver, år, opplag, sider
    Chichester, West Sussex United Kingdom: Wiley-Blackwell, 2008
    Emneord
    adverse drug reactions, epidemiology, mortality, population based study
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-12847 (URN)10.1111/j.1365-2125.2007.03064.x (DOI)000253883800017 ()
    Tilgjengelig fra: 2007-12-19 Laget: 2007-12-19 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    2. Fatal intoxications in a Swedish forensic autopsy material during 1992-2002
    Åpne denne publikasjonen i ny fane eller vindu >>Fatal intoxications in a Swedish forensic autopsy material during 1992-2002
    2004 (engelsk)Inngår i: Forensic Science International, ISSN 0379-0738, Vol. 143, nr 1, s. 53-59Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Compilations of substances detected in fatal intoxications are important in order to observe changes in intoxication patterns, to monitor effects of preventive work and to discover new trends in drug usage. The aim of the present study was to describe the current pattern of substances detected in fatal intoxications in Sweden. Fatal intoxications investigated at the Department of Forensic Chemistry, Linköping, Sweden, during 1992–2002, were analysed. All suicides, uncertain cases and accidents where the cause of death were fatal intoxications (ICD-9: E950, E980 and E859) were included and substances detected in more than 50 fatal intoxications (in femoral blood) were listed. For each substance, a cut off value was set, above which concentrations were considered toxic. Fatal intoxications were detected by forensic-chemical analyses in 12% (6998/60,314) of the forensic autopsies during the study period. Among the suicides, an average of 3.8 substances were detected per case, the corresponding figure for uncertain cases and accidents were 3.5 and 4.1 substances, respectively. Ethanol was by far the most frequently detected substance, detected in 43% (3039) of the fatal intoxications, of which 32% (960) had toxic concentrations, followed by propoxyphene, detected in 27% (1863) of the fatal intoxications of which 74% (1370) had toxic concentrations. The number of cases where ethanol and propoxyphene were detected decreased during the study period. Moreover, other CNS-active drugs such as antidepressants, analgesics and anxiolytics were also frequently detected. The drugs with high proportions of cases with toxic concentrations detected were propoxyphene, amitriptyline, zolpidem, carisoprodol, alprazolam, thioridazine, methadone and ketobemidone. Selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) were detected in 12% (833) and 10% (665), respectively. A significantly (P<0.001) higher proportion of cases where TCA were detected had toxic concentrations when compared with cases where SSRI were detected (64% versus 31%).

    Emneord
    Forensic science, Forensic chemistry, Fatal intoxications, Postmortem, Toxicology
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-12848 (URN)10.1016/j.forsciint.2004.02.010 (DOI)
    Tilgjengelig fra: 2007-12-19 Laget: 2007-12-19 Sist oppdatert: 2009-08-19
    3. Cerebral haemorrhage induced by warfarin - the influence of drug-drug interactions
    Åpne denne publikasjonen i ny fane eller vindu >>Cerebral haemorrhage induced by warfarin - the influence of drug-drug interactions
    2007 (engelsk)Inngår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, ISSN 1, Vol. 16, nr 3, s. 309-315Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: To evaluate the frequency, severity and preventability of warfarin-induced cerebral haemorrhages due to warfarin and warfarin-drug interactions in patients living in the county of Östergötland, Sweden.

    Methods: All patients with a diagnosed cerebral haemorrhage at three hospitals during the period 2000-2002 were identified. Medical records were studied retrospectively to evaluate whether warfarin and warfarin-drug interactions could have caused the cerebral haemorrhage. The proportion of possibly avoidable cases due to drug interactions was estimated.

    Results: Among 593 patients with cerebral haemorrhage, 59 (10%) were assessed as related to warfarin treatment. This imply an incidence of 1.7/100 000 treatment years. Of the 59 cases, 26 (44%) had a fatal outcome, compared to 136 (25%) among the non-warfarin patients (p < 0.01). A warfarin-drug interaction could have contributed to the haemorrhage in 24 (41%) of the warfarin patients and in 7 of these (12%) the bleeding complication was considered being possible to avoid.

    Conclusions: Warfarin-induced cerebral haemorrhages are a major clinical problem with a high fatality rate. Almost half of the cases was related to a warfarin-drug interaction. A significant proportion of warfarin-related cerebral haemorrhages might have been prevented if greater caution had been taken when prescribing drugs known to interact with warfarin.

    Emneord
    warfarin, cerebral haemorrhage, drug interactions, prevention
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-12849 (URN)10.1002/pds.1291 (DOI)
    Tilgjengelig fra: 2007-12-19 Laget: 2007-12-19 Sist oppdatert: 2017-12-14
    4. Antipsychotics and risk for venous thromboembolism: A population based case-control study
    Åpne denne publikasjonen i ny fane eller vindu >>Antipsychotics and risk for venous thromboembolism: A population based case-control study
    Vise andre…
    2009 (engelsk)Inngår i: Clinical Epidemiology, ISSN 1179-1349, Vol. 1, s. 19-26Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    During the last decade, the risk of venous thromboembolism (VTE) has been reported in users of antipsychotic drugs. However, the reports have been inconclusive. This study aimed to determine the relative risk of VTE in antipsychotic drug users. Using data from medical databases in North Jutland and Aarhus Counties, Denmark, and the Danish Civil Registration System, we identified 5,999 cases with a first-time diagnosis of VTE and, based on risk set sampling, 59,990 sex- and age-matched population controls during 1997–2005. Users of antipsychotic drugs were identified from population-based prescription databases and categorized based on filled prescriptions prior to admission date for VTE or index date for controls as current (at least one prescription within 90 days), recent (at least one prescription within 91–180 days), former (at least one prescription within 181–365 days) or nonusers (no recorded prescription within 365 days). Compared with nonusers, current users of any antipsychotic drugs had an increased risk of VTE (adjusted relative risk [ARR]: 1.99, 95% confidence interval [CI]: 1.69–2.34). Former users of any antipsychotic drugs had a nonsignificant elevated risk of VTE compared with nonusers (ARR: 1.54, 95% CI: 0.99–2.40, p-value: 0.056). In conclusion, users of antipsychotic drugs have an increased risk of VTE, compared with nonusers, which might be due to the treatment itself, to lifestyle factors, to the underlying disease, or to residual confounding.

    Emneord
    antipsychotic agents, venous thromboembolism, adverse effects, case-control study
    Identifikatorer
    urn:nbn:se:liu:diva-12850 (URN)
    Merknad
    Original Publication: Anna K. Jönsson, Erzsebet Horváth-Puhó, Staffan Hägg, Lars Pedersen and Henrik T Sörensen, Antipsychotics and risk for venous thromboembolism: A population based case-control study, 2009, Clinical Epidemiology, (1), 19-26. http://www.dovepress.com/antipsychotics-and-risk-of-venous-thromboembolism-a-population-based-c-peer-reviewed-article-CLEP Licensee: Dove Medical Press http://www.dovepress.com/index.php Tilgjengelig fra: 2007-12-19 Laget: 2007-12-19 Sist oppdatert: 2010-01-29
    5. Antipsychotics associated with pulmonary embolism in a Swedish medico-legal autopsy series
    Åpne denne publikasjonen i ny fane eller vindu >>Antipsychotics associated with pulmonary embolism in a Swedish medico-legal autopsy series
    Vise andre…
    Manuskript (Annet vitenskapelig)
    Identifikatorer
    urn:nbn:se:liu:diva-12851 (URN)
    Tilgjengelig fra: 2007-12-19 Laget: 2007-12-19 Sist oppdatert: 2010-01-13
  • 52.
    Karlsson, Camilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Rehman, Faazal
    NIH, MD 20892 USA.
    Damdazic, Ruslan
    NIH, MD 20892 USA.
    Atkins, Alison Lynn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Schank, Jesse R.
    University of Georgia, GA 30602 USA.
    Gehlert, Donald R.
    Eli Lilly and Co, IN 46285 USA.
    Steensland, Pia
    Karolinska Institute, Sweden.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation2016Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, nr 12, s. 2355-2363Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh. In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol. We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice. Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh.

  • 53.
    Karlsson, Louise
    et al.
    Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Zackrisson, Anna Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Josefsson, M
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden; 3Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
    Carlsson, Björn
    Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Forensic Genetics andForensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik C
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.2015Inngår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 15, nr 2, s. 165-71Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We investigated whether polymorphisms in the CYP2D6 and CYP2C19 genes influence the metabolic ratios and enantiomeric S/R ratios of venlafaxine (VEN) and its metabolites O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (DDV) in blood from forensic autopsy cases. In all, 94 postmortem cases found positive for VEN during toxicological screening were included. The CYP2D6 genotype was shown to significantly influence the ODV/VEN (P=0.003), DDV/NDV (P=0.010) and DDV/ODV (P=0.034) ratios. The DDV/ODV (P=0.013) and DDV/VEN (P=0.021) ratios were significantly influenced by the CYP2C19 genotype. The S/R ratios of VEN were significantly influenced by both CYP2D6 and CYP2C19 genotypes. CYP2D6 poor metabolizers (PMs) had lower S/R VEN ratios and CYP2C19 PMs had high S/R ratios of VEN in comparison. Our results show that the CYP2D6 genotype influences the O-demethylation whereas CYP2C19 influences the N-demethylation of VEN and its metabolites. In addition, we show a stereoselective metabolism where CYP2D6 favours the R-enantiomer whereas CYP2C19 favours the S-enantiomer.

  • 54.
    Klawonn, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Molecular Mechanisms of Reward and Aversion2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Various molecular pathways in the brain shape our understanding of good and bad, as well as our motivation to seek and avoid such stimuli. This work evolves around how systemic inflammation causes aversion; and why general unpleasant states such as sickness, stress, pain and nausea are encoded by our brain as undesirable; and contrary to these questions, how drugs of abuse can subjugate the motivational neurocircuitry of the brain. A common feature of these various disease states is involvement of the motivational neurocircuitry - from mesolimbic to striatonigral pathways. Having an intact motivational system is what helps us evade negative outcomes and approach natural positive reinforcers, which is essential for our survival. During disease-states the motivational neurocircuitry may be overthrown by the molecular mechanisms that originally were meant to aid us.

    In study I, to investigate how inflammation is perceived as aversive, we used a behavioral test based on Pavlovian place conditioning with the aversive inflammatory stimulus E. coli lipopolysaccharide (LPS). Using a combination of cell-type specific gene deletions, pharmacology, and chemogenetics, we uncovered that systemic inflammation triggered aversion by MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Moreover, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, inflammation-induced aversion was not an indirect consequence of fever or anorexia but constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic circuitry is a key mechanism underlying inflammation-induced aversion.

    In study II, we investigate the role of peripheral IFN-γ in LPS induced conditioned place aversion by employing a strategy based on global and cell-type specific gene deletions, combined with measures of gene-expression. LPS induced IFN-ɣ expression in the blood, and deletion of IFN-ɣ or its receptor prevented conditioned place aversion (CPA) to LPS. LPS increased the expression of chemokine Cxcl10 in the striatum of normal mice. This induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion. Collectively, these findings demonstrate that circulating IFN-ɣ binding to receptors on brain endothelial cells which induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.

    In study III, we explored the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice in CPA to various stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain and kappa opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference towards most of the aversive stimuli, but were indifferent to pain. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine-dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were re-expressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in a MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

    The neurotransmitter acetylcholine has been implied in reward learning and drug addiction. However, the role of cholinergic receptor subtypes in such processes remains elusive. In study IV we investigated the function of muscarinic M4Rs on dopamine D1R expressing neurons and acetylcholinergic neurons, using transgenic mice in various reward-enforced behaviors and in a “waiting”-impulsivity test. Mice lacking M4-receptors from D1-receptor expressing neurons exhibited an escalated reward seeking phenotype towards cocaine and natural reward, in Pavlovian conditioning and an operant self-administration task, respectively. In addition, the M4-D1RCre mice showed impaired waiting impulsivity in the 5-choice-serial-reaction-time-task. On the contrary, mice without M4Rs in acetylcholinergic neurons were unable to learn positive reinforcement to natural reward and cocaine, in an operant runway paradigm and in Pavlovian conditioning.  Immediate early gene expression mirrored the behavioral findings arising from M4R-D1R knockout, as cocaine induced cFos and FosB was significantly increased in the forebrain of M4-D1RCre mice, whereas it remained normal in the M4R-ChatCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality.

    Delarbeid
    1. Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
    Åpne denne publikasjonen i ny fane eller vindu >>Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
    Vise andre…
    2016 (engelsk)Inngår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, nr 2, s. 695-705Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E-2 (PGE(2)) synthesis. Further, we showed that inflammation-induced PGE(2) targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE(2)-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

    sted, utgiver, år, opplag, sider
    AMER SOC CLINICAL INVESTIGATION INC, 2016
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-126263 (URN)10.1172/JCI83844 (DOI)000370677300029 ()26690700 (PubMedID)
    Merknad

    Funding Agencies|European Research Council (ERC); Swedish Medical Research Council; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; County Council of Ostergotland; Swedish Cancer Foundation; Veterans Administration Merit award; NIH [NS33987, NS72337]

    Tilgjengelig fra: 2016-03-21 Laget: 2016-03-21 Sist oppdatert: 2019-04-29bibliografisk kontrollert
    2. Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion
    Åpne denne publikasjonen i ny fane eller vindu >>Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion
    2018 (engelsk)Inngår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 67, s. 54-58Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-ɣ (IFN-ɣ) in the aversive response to systemic inflammation induced by a low dose (10μg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-ɣ expression in the blood and deletion of IFN-ɣ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-ɣ action. Collectively, these findings show that circulating IFN-ɣ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.

    sted, utgiver, år, opplag, sider
    Maryland Heights: Academic Press, 2018
    Emneord
    Aversion; Behavior; Chemokines; Depression; Endothelium; Interferon; Lipopolysaccharide; Sickness
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-143812 (URN)10.1016/j.bbi.2017.08.020 (DOI)000416879100007 ()28864260 (PubMedID)2-s2.0-85028972384 (Scopus ID)
    Merknad

    Funding agencies: European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg foundation; Swedish Brain foundation; Parkinsonstiftelsen; Region Ostergotland

    Tilgjengelig fra: 2017-12-19 Laget: 2017-12-19 Sist oppdatert: 2019-04-10bibliografisk kontrollert
  • 55.
    Klawonn, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Nilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Rådberg, Carl F.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Lindström, Sarah
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Ericson, Mia
    University of Gothenburg, Sweden.
    Granseth, Björn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Fritz, Michael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum2017Inngår i: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, artikkel-id 714Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatmentresistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction. We examined the effect of the sigma-2 receptor agonist Siramesine (Lu 28-179) on cocaine-associated locomotion, Pavlovian learning, and reward neurocircuitry using electrophysiology recordings and in vivo microdialysis. We found that Siramesine significantly attenuated conditioned place preference acquisition and expression, as well as it completely blocked cocaine-primed reinstatement. Siramesine, in a similar manner as the selective sigma-1 receptor antagonist BD 1063, decreased acute locomotor responses to cocaine. Immunohistochemistry suggests co-expression of progesterone receptor membrane component 1/sigma-2 receptors and vesicular glutamate transporter 1 in presynaptic boutons of the nucleus accumbens (NAc). Whole-cell voltage clamp recordings of neurons in the NAc indicated that Siramesine decreases the presynaptic release probability of glutamate. Further, we demonstrated, via in vivo microdialysis, that Siramesine significantly decreased cocaine-evoked dopamine release in the striatum of freely moving mice. Collectively, these findings demonstrate that sigma-2 receptors regulate neurocircuitry responsible for positive reinforcement and thereby play a role in cocaine-reinforced Pavlovian behaviors.

  • 56.
    Kronstrand, Robert
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Forsman, Malin
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden .
    Roman, Markus
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden .
    A Screening Method for 30 Drugs in Hair Using Ultrahigh-Performance Liquid Chromatography Time-of-Flight Mass Spectrometry2013Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 35, nr 3, s. 288-295Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: The objectives of this study were to develop and to validate a qualitative screening method that met the new Society of Hair Testing (SoHT) guideline criteria for thresholds. less thanbrgreater than less thanbrgreater thanMethods: Extraction of 20 mg hair was performed by a previously validated procedure using overnight incubation in a mixture of methanol:acetonitrile:formiate buffer pH 3 (10:10:80). Analysis was performed on an Agilent 6540 quadrupole time-of-flight mass spectrometer in combination with an Agilent 1290 Infinity ultrahigh-performance liquid chromatography system. Separation was achieved with a 12-minute linear gradient chromatography on a high-strength silica T3 column at acidic conditions. An in-house database containing 30 compounds from the groups amphetamines, opiates, opioids, cocaine, benzodiazepines, and other sedatives including 6 deuterated internal standards was built by analyzing solutions from certified standards. Data were extracted using mass accuracy of +/- 10 ppm, retention time deviation of +/- 0.15 minutes, and area of andgt;= 30,000 counts. Identification was based on scoring of retention time, accurate mass measurement, and isotopic pattern. Validation included selectivity, repeatability of analyte area, and the scoring parameters at the proposed thresholds and a method comparison with the present liquid chromatography-mass spectrometry-mass spectrometry method using 50 authentic hair samples. A daily cutoff calibrator was used to identify positive samples. less thanbrgreater than less thanbrgreater thanResults: All cutoffs could be met with imprecisions of less than 5% for most parameters and analytes. Hair from drug-free subjects did not produce any positive results and the method comparison agreed in more than 90% of the cases. less thanbrgreater than less thanbrgreater thanConclusions: We conclude that the developed method meets the criteria of the new SoHT guidelines for screening cutoffs. Even though no thresholds have been suggested for benzodiazepines, we conclude that thresholds between 0.05 and 0.1 ng/mg should be sufficient to determine regular use of these substances.

  • 57.
    Kronstrand, Robert
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Roman, Markus
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Thelander, Gunilla
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Eriksson, Anders
    Section of Forensic Medicine, Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden.
    Unintentional Fatal Intoxications with Mitragynine and O-Desmethyltramadol from the Herbal Blend Krypton2011Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 35, nr 4, s. 242-247Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The leaves of Kratom, a medicinal plant in Southeast Asia, have been used as an herbal drug for a long time. At least one of the alkaloids present in Kratom, mitragynine, is a mu-receptor agonist. Both Kratom and an additional preparation called Krypton are available via the internet. It seems to consist of powdered Kratom leaves with another mu-receptor agonist, O-desmethyltramadol, added. O-Desmethyltramadol is an active metabolite of tramadol, a commonly prescribed analgesic.We present nine cases of intoxication, occurring in a period of less than one year, where both mitragynine and O-desmethyltramadol were detected in the postmortem blood samples. Neither tramadol nor N-desmethyltramadol was present in these samples, which implies that the ingested drug was O-desmethyltramadol. The blood concentrations of mitragynine, determined by ultra-performance liquid chromatography-tandem mass spectrometry, ranged from 0.02 to 0.18 µg/g, and O-desmethyltramadol concentrations, determined by gas chromatography with nitrogen-specific detection, ranged from 0.4 to 4.3 µg/g. We believe that the addition of the potent mu-receptor agonist O-desmethyltramadol to powdered leaves from Kratom contributed to the unintentional death of the nine cases presented and conclude that intake of Krypton is not as harmless as it often is described on internet websites.

  • 58.
    Krzemieniecki, Krzysztof
    et al.
    Krakow, Poland.
    Szpyt, Elżbieta
    Krakow, Poland.
    Rashedi, Iran
    Tehran, Iran and Canada.
    Gawron, Katarzyna
    808 Zabrze, Poland.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Targeting of solid tumors and blood malignancies by antibody-based therapies - EGFR-pathway as an example2006Inngår i: Central European Journal of Biology, ISSN 1895-104X, E-ISSN 1644-3632, Vol. 1, nr 2, s. 167-182Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    A well-coordinated interaction between extracellular signals and intracellular response forms the basis of life within multicellular organisms, with growth factors playing a crucial role in these interactions. Discoveries in recent years have shown that components of the Epidermal Growth Factor (EGF) signaling system have frequently been used by cancer cells to autonomously provide survival and proliferation signals. The main focus of this review is the ErbB epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases including ErbB1/EGFR, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4 as therapeutic targets. Since the ErbB receptor family regulates cell proliferation through the Ras-mitogen-activated protein kinase (RAS/MAPK) pathway, and cell survival and transformation through the phosphatidylinositol 3-kinase (PI3K/AKT) pathway, pharmacological targeting of these pathways is also discussed. We will also address the clinical studies that have been conducted to evaluate antibody-based therapies mostly on solid tumors and hematologic malignancies. (c) Versita Warsaw and Springer-Verlag Berlin Heidelberg. All rights reserved.

  • 59.
    Kumar Jeengar, Manish
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. National Institute Pharmaceut Educ and Research Institute, India.
    Thummuri, Dinesh
    National Institute Pharmaceut Educ and Research Institute, India.
    Magnusson, Mattias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Naidu, V. G. M.
    National Institute Pharmaceut Educ and Research Institute, India; National Institute Pharmaceut Educ and Research Institute, India.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Uridine Ameliorates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 3924Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Uridine, one of the four components that comprise RNA, has attracted attention as a novel therapeutic modulator of inflammation. However, very little is known about its effect on intestinal inflammation. The aim of the present study was to investigate the potential protective effect of intracolonic administered uridine against DSS induced colitis in male C57BL/6 mice. Intracolonic instillation of 3 doses of uridine 1 mg/Kg (lower dose), 5 mg/Kg (medium dose), and 10 mg/Kg (higher dose) in saline was performed daily. Uridine at medium and high dose significantly reduced the severity of colitis (DAI score) and alleviated the macroscopic and microscopic signs of the disease. The levels of proinflammatory cytokines IL-6, IL-1 beta and TNF in serum as well as mRNA expression in colon were significantly reduced in the uridine treated groups. Moreover, colon tissue myloperoxidase activities, protein expression of IL-6, TNF-alpha, COX-2, P-NFkB and P-Ikk-alpha beta in the colon tissues were significantly reduced in medium and high dose groups. These findings demonstrated that local administration of uridine alleviated experimental colitis in male C57BL/6 mice accompanied by the inhibition of neutrophil infiltration and NF-kappa B signaling. Thus, Uridine may be a promising candidate for future use in the treatment of inflammatory bowel disease.

  • 60.
    Kälvegren, Hanna
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    The Role of Chlamydia pneumoniae-induced Platelet Activation in Cardiovascular Disease: In vitro and In vivo studies2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The common risk factors for atherosclerosis, such as obesity, high cholesterol levels, sedentary lifestyle, diabetes and high alcohol intake, only explain approximately 50% of cardiovascular disease events. It is thereby important to identify new mechanisms that can stimulate the process of atherosclerosis. During the past decades, a wide range of investigations have demonstrated connections between infections by the respiratory bacterium Chlamydia pneumoniae and atherosclerosis. Earlier studies have focused on the interaction between C. pneumoniae and monocytes/macrophages, T-lymphocytes, smooth muscle cells and endothelial cells, which are present in the atherosclerotic plaque. However, another important player in atherosclerosis and which is also present in the plaques is the platelet. Activation of platelets can stimulate both initiation and progression of atherosclerosis and thrombosis, which is the ultimate endpoint of the disease. The aim of the present thesis was to investigate the capacity of C. pneumoniae to activate platelets and its role in atherosclerosis.

    The results show that C. pneumoniae at low concentrations binds to platelets and stimulates platelet aggregation, secretion, reactive oxygen species (ROS) production and oxidation of low-density lipoproteins (LDL), and that these effects are mediated by lipopolysaccharide (LPS). Activation of protein kinase C, nitric oxide synthase and 12-lipoxygenase (12-LOX) was required for platelet ROS production, whereas platelet aggregation was dependent on activation of GpIIb/IIIa. Pharmacological studies showed that the C. pneumoniae-induced platelet activation is prevented by inhibitors against 12-LOX, platelet activating factor (PAF) and the purinergic P2Y1 and P2Y12 receptors, but not against cyclooxygenase (COX). These findings were completely opposite to the effects of these inhibitors on collagen-stimulated platelets. We also present data from a clinical study indicating that percutaneous coronary intervention (PCI or balloon dilatation) leads to release of C. pneumoniae into the circulation, which causes platelet activation and LDL oxidation.

    In conclusion, these data support a role for C. pneumoniae-induced platelet activation in the process of atherosclerosis. Stimulation of platelets by C. pneumoniae leads to release of growth factors and cytokines, oxidation of LDL and platelet aggregation, which are processes that can stimulate both atherosclerosis and thrombosis. Development of novel drugs that prevent C. pneumoniae-platelet interaction by inhibiting 12-LOX and/or PAF, may be important in the future treatment of cardiovascular disease.

    Delarbeid
    1. Chlamydia pneumoniae binds to platelets and triggers P-selectin expression and aggregation: A causal role in cardiovascular disease?
    Åpne denne publikasjonen i ny fane eller vindu >>Chlamydia pneumoniae binds to platelets and triggers P-selectin expression and aggregation: A causal role in cardiovascular disease?
    2003 (engelsk)Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 23, nr 9, s. 1677-1683Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective - Evidence linking Chlamydia pneumoniae to atherosclerotic cardiovascular disease is expanding. Platelets are considered to play an essential role in cardiovascular diseases, however, so far platelets have not been associated with an infectious cause of atherosclerosis. This study aims to clarify the interaction between Cpneumoniae and platelets and possibly present a novel mechanism in the pathogenesis of atherosclerosis.

    Methods and Results - The effects of C pneumoniae on platelet aggregation and secretion were assessed with lumiaggregometry, and the ability of C pneumoniae to bind to platelets and stimulate expression of P-selectin was analyzed with flow cytometry. We found that Cpneumoniae, at a chlamydia:platelet ratio of 1:15, adheres to platelets and triggers P-selectin expression after 1 minute and causes an extensive aggregation and ATP secretion after 20 minutes of incubation. Inhibition of glycoprotein IIb/IIIa with Arg-Gly-Asp-Ser or abciximab markedly reduced C pneumoniae-induced platelet aggregation. Exposure of C pneumoniae to polymyxin B, but not elevated temperature, abolished the stimulatory effects on platelet activation, suggesting that chlamydial lipopolysaccharide has an active role. In contrast, other tested bacteria had no or only moderate effects on platelet functions.

    Conclusion - Our findings demonstrate a new concept of how C pneumoniae activates platelets and thereby may cause atherosclerosis and thrombotic vascular occlusion.

     

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14386 (URN)10.1161/01.ATV.0000084810.52464.D5 (DOI)
    Tilgjengelig fra: 2007-04-20 Laget: 2007-04-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Chlamydia pneumoniae induces nitric oxide synthase and lipoxygenase-dependent production of reactive oxygen species in platelets — effects on oxidation of low-density lipoproteins.
    Åpne denne publikasjonen i ny fane eller vindu >>Chlamydia pneumoniae induces nitric oxide synthase and lipoxygenase-dependent production of reactive oxygen species in platelets — effects on oxidation of low-density lipoproteins.
    Vise andre…
    2005 (engelsk)Inngår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 94, nr 2, s. 327-335Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    There is increasing evidence that Chlamydia pneumoniae is linked to atherosclerosis and thrombosis. In this regard, we have recently shown that C. pneumoniae stimulates platelet aggregation and secretion, which may play an important role in the progress of atherosclerosis and in thrombotic vascular occlusion. The aims of the present study were to investigate the effects of C. pneumoniae on platelet-mediated formation of reactive oxygen species (ROS) and oxidation of low-density lipoprotein (LDL) in vitro. ROS production was registered as changes in 2´,7`-dichlorofluorescin- fluorescence in platelets with flow cytometry. LDL-oxidation was determined by measuring thiobarbituric acid reactive substances (TBARs). We found that C. pneumoniae stimulated platelet production of ROS.Polymyxin B treatment of C. pneumoniae, but not elevated temperature, abolished the stimulatory effects on platelet ROS- production, which suggests that chlamydial lipopolysaccharide has an important role. In hibition of nitric oxide synthase with nitro-L-arginine, lipoxygenase with 5,8,11-eicosatriynoic acid and protein kinase C with GF 109203X significantly lowered the production of radicals. In contrast, inhibition of NADPH-oxidase with di-phenyleneiodonium (DPI) did not affect the C. pneumoniae induced ROS-production. These findings suggest that the activities of nitric oxide synthase and lipoxygenase are the sources for ROS and that the generation is dependent of the activity of protein kinase C.The C. pneumoniae-induced ROS-production in platelets was associated with an extensive oxidation of LDL, which was significantly higher compared to the effect obtained by separate exposure of LDL to C. pneumoniae or platelets. In conclusion, C. pneumoniae interaction with platelets leading to aggregation, ROS-production and oxidative damage on LDL, may play a crucial role in the development of atherosclerotic cardiovascular disease.

    Emneord
    Atherosclerosis, bacteria-cell interaction, oxygen radical, LPS, thrombosis
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14387 (URN)10.1160/TH04-06-0360 (DOI)
    Tilgjengelig fra: 2007-04-20 Laget: 2007-04-20
    3. Correlation between rises in Chlamydia pneumoniae-specific antibodies, platelet activation and lipid peroxidation after percutaneous coronary intervention.
    Åpne denne publikasjonen i ny fane eller vindu >>Correlation between rises in Chlamydia pneumoniae-specific antibodies, platelet activation and lipid peroxidation after percutaneous coronary intervention.
    Vise andre…
    2008 (engelsk)Inngår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 27, nr 7, s. 503-511Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We recently showed that Chlamydia pneumoniae activates platelets in vitro, with an associated oxidation of low-density lipoproteins. The aim of this study was to investigate whether C. pneumoniae is released during percutaneous coronary intervention (PCI) and, thereby, causes platelet activation and lipid peroxidation. Seventy-three patients undergoing coronary angiography and following PCI or coronary artery bypass graft (CABG) and 57 controls were included in the study. C. pneumoniae antibodies, serotonin and lipid peroxidation were measured before and 24 h, 1 month and 6 months after angiography. The results show that serum C. pneumoniae IgA concentrations were significantly higher in patients than in the controls. Furthermore, in 38% of the C. pneumoniae IgG positive patients, the C. pneumoniae IgG concentration increased 1 month after PCI. The levels of C. pneumoniae IgG antibodies 1 month after PCI correlated with plasma-lipid peroxidation (r = 0.91, P < 0.0001) and platelet-derived serotonin (r = 0.62, P = 0.02). There was no elevation in the total serum IgG 1 month after PCI. In conclusion, the present results suggest that PCI treatment of coronary stenosis releases C. pneumoniae from the atherosclerotic lesions, which leads to platelet activation and lipid peroxidation.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14388 (URN)10.1007/s10096-008-0465-y (DOI)
    Tilgjengelig fra: 2007-04-20 Laget: 2007-04-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    4. Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors.
    Åpne denne publikasjonen i ny fane eller vindu >>Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors.
    2007 (engelsk)Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 566, nr 1-3, s. 20-27Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Chlamydia pneumoniae is a respiratory pathogen that has been linked to cardiovascular disease. We have recently shown that C. pneumoniae activates platelets, leading to oxidation of low-density lipoproteins. The aim of the present study was to evaluate the inhibitory effects of different pharmacological agents on platelet aggregation and secretion induced by C. pneumoniae.

    Platelet interaction with C. pneumoniae was studied by analyzing platelet aggregation and ATP-secretion with Lumi-aggregometry.

    Platelet aggregation and ATP-secretion induced by C. pneumoniae was markedly inhibited by the NO-donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP), an effect that was counteracted by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Pre-treatment of platelets with the 12-lipoxygenase (12-LOX) inhibitors cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) and 5,6,7-trikydroxyflavone (baicalein) completely blocked the activation, whereas the cyclooxygenase (COX) inhibitors 2-acetyloxybenzoic acid (aspirin) and (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-9-methyl-10,10-dioxo-10$l^(6)thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one (piroxicam) had no inhibitory effects. Opposite to C. pneumoniae-induced activation, platelets stimulated by collagen were inhibited by the COX-inhibitors but were unaffected by the 12-LOX-inhibitors. The platelet activating factor (PAF) antagonist Ginkgolide B blocked the C. pneumoniae-induced platelet activation, whereas the responses to collagen were unaffected. Furthermore, the P2Y1 and P2Y12 purinergic receptor antagonists 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179) and N(6)-(2-methyl-thioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (cangrelor) inhibited the aggregation and secretion caused by C. pneumoniae.

    It is well-known that the efficacy of COX inhibitors in the prevention and treatment of cardiovascular disease varies between different patients, and that patients with low responses to aspirin have a higher risk to encounter cardiovascular events. The findings in this study showing that platelets stimulated by C. pneumoniae are unaffected by COX inhibitors but sensitive to 12-LOX inhibitors, may thus be of importance in future management of atherosclerosis and thrombosis.

    Emneord
    Chlamydia pneumoniae, Platelet, Aggregation, Lipoxygenase, Cyclooxygenase
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14389 (URN)10.1016/j.ejphar.2007.03.024 (DOI)
    Tilgjengelig fra: 2007-04-20 Laget: 2007-04-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert
  • 61.
    Lahdenperä, Anne
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Ljungberg, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Lundberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Korpela, Riitta
    Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Vaarala, Outi
    National Institute Health and Welf, Finland .
    Probiotics and innate immune response in infants2014Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We studied the effects of probiotic treatment on the innate immune system during infancy. The study included a subgroup of infants recruited to the pilot study testing the feasibility of probiotics intervention in infants with genetic risk of type 1 diabetes (T1D). A mixture of Lactobacillus rhamnosus GG (5 x 109 cfu), Lactobacillus rhamnosus LC705 (5 x 109 cfu), Bifidobacterium breve Bbi99 (2 x 108 cfu) and Propionibacterium freudenreichii ssp. Shermani JS (2 x 109 cfu) was given to the infants beginning one to three weeks after birth until the age of 6 months. Blood samples were drawn at the age of 6, 12 and 24 months for the analyses of beta-cell autoantibodies and the phenotype and stimulation response of monocytes with flow-cytometry, including surface markers on circulating CD14+ monocytes and expression of co-stimulatory markers on CD14+ monocytes as response to stimulation with lipoteichoic acid (LTA) and lipopolysaccharide (LPS). Also gene expression of toll-like receptor (TLR) signalling molecules was studied in the peripheral blood mononuclear cell (PBMC) population.

    In the children who received probiotics the number of circulating CD14+ monocytes expressing CD58 was reduced at the age of 6 months, and a tendency for a decreased induction of CCR5, CD80 and CD58 expressing monocytes as response to LTA was seen when compared to the children who received placebo. At the age of 12 months, the number of monocytes expressing CCR5 was decreased in the probiotic group, and a decreased spontaneous expression of TNFRSF1A and an increased spontaneous expression of TLR9 was observed in the PBMC from the children treated with probiotics. In the whole study group, the numbers of circulating monocytes expressing CD80 increased with age as well as the induction of CCR5, CD80 and CD58 on monocytes as response to stimulation. By the age of 24 months one child in both groups developed multiple autoantibodies.

    We demonstrated that probiotics modulated the activation stage and stimulation response of monocytes, and that prolonged effects of the treatment were seen at the age of 12 months. The findings suggest that early microbial exposure may program the function of the innate immune system for later life.

  • 62.
    Liin, Sara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Lund, Per-Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Larsson, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Brask, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors2018Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, nr 8, s. 1215-1230Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential-generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.

  • 63.
    Lin, Qing
    et al.
    Sichuan Univ, Peoples R China; Univ Cambridge, England.
    Qu, Mengke
    Sichuan Univ, Peoples R China.
    Patra, Hirak Kumar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Univ Cambridge, England; Univ Cambridge, England.
    He, Shanshan
    Sichuan Univ, Peoples R China.
    Wang, Luyao
    Sichuan Univ, Peoples R China.
    Hua, Xun
    Sichuan Univ, Peoples R China; CQ MEDVT CO LTD, Peoples R China.
    Xiao, Linyu
    Sichuan Univ, Peoples R China.
    Fu, Yu
    Sichuan Univ, Peoples R China.
    Gong, Tao
    Sichuan Univ, Peoples R China.
    He, Qin
    Sichuan Univ, Peoples R China.
    Zhang, Ling
    Sichuan Univ, Peoples R China.
    Sun, Xun
    Sichuan Univ, Peoples R China.
    Zhang, Zhirong
    Sichuan Univ, Peoples R China.
    Mechanistic and therapeutic study of novel anti-tumor function of natural compound imperialine for treating non-small cell lung cancer2020Inngår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 247, artikkel-id 112283Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ethnopharmacological relevance: Bulbus Fritillaria cirrhosa D. Don (BFC) is a Chinese traditional herbal medicine that has long been used as an indispensable component in herbal prescriptions for bronchopulmonary diseases due to its well-established strong anti-inflammation and pulmonary harmonizing effects. Interestingly, there are few case reports in traditional Chinese medicine available where they found it to contribute in anti-tumor therapies. Imperialine is one of the most favored active substances extracted from BFC and has been widely recognized as an anti-inflammatory agent. Aim of the study: The aim of the current work is to provide first-hand evidences both in vitro and in vivo showing that imperialine exerts anti-cancer effects against non-small cell lung cancer (NSCLC), and to explore the molecular mechanism of this anti-tumor activity. It is also necessary to examine its systemic toxicity, and to investigate how to develop strategies for feasible clinical translation of imperialine. Materials and methods: To investigate anti-NSCLC efficacy of imperialine using both in vitro and in vivo methods where A549 cell line were chosen as in vitro model NSCLC cells and A549 tumor-bearing mouse model was constructed for in vivo study. The detailed underlying anti-cancer mechanism has been systematically explored for the first time through a comprehensive set of molecular biology methods mainly including immunohistochemistry, western blot and enzyme-linked immunosorbent assays. The toxicity profile of imperialine treatments were evaluated using healthy nude mice by examining hemogram and histopathology. An imperialine-loaded liposomal drug delivery system was developed using thin film hydration method to evaluate target specific delivery. Results: The results showed that imperialine could suppress both NSCLC tumor and associated inflammation through an inflammation-cancer feedback loop in which NF-kappa B activity was dramatically inhibited by imperialine. The NSCLC-targeting liposomal system was successfully developed for targeted drug delivery. The developed platform could favorably enhance imperialine cellular uptake and in vivo accumulation at tumor sites, thus improving overall anti-tumor effect. The toxicity assays revealed imperialine treatments did not significantly disturb blood cell counts in mice or exert any significant damage to the main organs. Conclusions: Imperialine exerts anti-cancer effects against NSCLC both in vitro and in vivo, and this previously unknown function is related to NF-kappa B centered inflammation-cancer feedback loop. Imperialine mediated anticancer activity is not through cytotoxicity and exhibit robust systemic safety. Furthermore, the liposome-based system we commenced would dramatically enhance therapeutic effects of imperialine while exhibiting extremely low side effects both on cellular and in NSCLC model. This work has identified imperialine as a promising novel anti-cancer compound and offered an efficient target-delivery solution that greatly facilitate practical use of imperialine.

  • 64.
    Lin, Qing
    et al.
    Sichuan Univ, Peoples R China; Univ Cambridge, England.
    Qu, Mengke
    Sichuan Univ, Peoples R China.
    Zhou, Bingjie
    Sichuan Univ, Peoples R China.
    Patra, Hirak Kumar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Univ Cambridge, England.
    Sun, Zihan
    Sichuan Univ, Peoples R China.
    Luo, Qiong
    Sichuan Univ, Peoples R China.
    Yang, Wenyu
    Sichuan Univ, Peoples R China.
    Wu, Yongcui
    Sichuan Univ, Peoples R China.
    Zhang, Yu
    Sichuan Univ, Peoples R China.
    Li, Lin
    Sichuan Univ, Peoples R China.
    Deng, Lang
    Sichuan Univ, Peoples R China.
    Wang, Leilei
    Sichuan Univ, Peoples R China.
    Gong, Tao
    Sichuan Univ, Peoples R China.
    He, Qin
    Sichuan Univ, Peoples R China.
    Zhang, Ling
    Sichuan Univ, Peoples R China.
    Sun, Xun
    Sichuan Univ, Peoples R China.
    Zhang, Zhirong
    Sichuan Univ, Peoples R China.
    Exosome-like nanoplatform modified with targeting ligand improves anti-cancer and anti-inflammation effects of imperialine2019Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 311, s. 104-116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Currently, most anti-cancer therapies are still haunted by serious and deleterious adverse effects. Here, we report a highly biocompatible tumor cell-targeting delivery systems utilizing exosome-like vesicles (ELVs) that delivers a low-toxicity anti-cancer agent imperialine against non-small cell lung cancer (NSCLC). First, we introduced a novel micelle-aided method to efficiently load imperialine into intact ELVs. Then, integrin alpha 3 beta 1-binding octapeptide cNGQGEQc was modified onto ELV platform for tumor targeting as integrin alpha 3 beta 1 is overexpressed on NSCLC cells. This system not only significantly improved imperialine tumor accumulation and retention, but also had extremely low systemic toxicity both in vitro and in vivo. Our discoveries offer new ways to utilize ELV more efficiently for both drug loading and targeting. The solid pharmacokinetics improvement and extraordinary safety of this system also highlight possibilities of alternative long course cancer therapies using similar strategies.

  • 65.
    Ljunggren, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Lipoproteomics: Environmental and Genetic Factors Affecting High-Density Lipoprotein (HDL)2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Lipoprotein particles act as lipid transporters in the blood stream, and measuring cholesterol content in specific subclasses of lipoprotein particles has long been, and still is, a frequently used tool to estimate the risk of cardiovascular disease (CVD). High-density lipoprotein (HDL) is a subclass of lipoproteins often regarded as providing protection against CVD via several functions including reverse cholesterol transport and anti-inflammatory capacities. However, the precise relationship between HDL cholesterol levels and health outcome is still unclear. Lately, new approaches to study HDL composition and function have therefore become more important.

    HDL function is to a large extent dependent on its proteome, containing more than 100 proteins. Investigating the proteome in individuals with altered gene expression for HDL-associated proteins or with known exposure to environmental contaminants may reveal new insights into how HDL metabolism is affected by various factors. This is of interest in order to better understand the role of HDL in CVD.

    Papers I and II focus on two different mutations in a structural HDL protein, apolipoprotein A-I (L202P and K131del), and one mutation in the scavenger receptor class B-1 (P297S), which is involved in selective lipid uptake of cholesterol mainly into hepatocytes and adrenal cells. The HDL proteome was analyzed using two-dimensional gel electrophoresis and mass spectrometry. The L202P mutation was identified in HDL of the heterozygote carriers together with a significant decrease of apolipoprotein E and increased zinc-alpha-2-glycoprotein. By contrast, the second apolipoprotein AI mutation (K131del) was associated with significantly elevated alpha-1-antitrypsin and transthyretin levels. Protein analyses of the scavenger receptor class B1 P297S heterozygotes showed a significant increase in HDL apoL-1 along with increased free apoE. The carriers showed no difference in antioxidative capability but a significant increase in apoA-I methionine oxidation.

    Papers III and IV focus on persistent organic pollutants that may influence HDL composition and function. These compounds accumulate in humans, and exposure has been linked to an increased risk of CVD. To provide a better understanding of the HDL system in relation to pollutants, a population living in a contaminated area was studied. Persistent organic pollutants in isolated HDL were quantified using high-resolution gas chromatography mass spectrometry and significantly increased levels were found in individuals with CVD as compared to healthy controls. Furthermore, there was a significant negative association between the pollutants and paraoxonase-1 anti-oxidant activity. Studying the proteome with nano-liquid chromatography tandem mass spectrometry led to the identification of 118 proteins in HDL, of which ten were significantly associated with the persistent organic pollutants.

    In summary, the present studies demonstrate protein pattern alterations in HDL associated with inherited genetic variants or pollutant exposure. The studies also provide a set of methods that are useful tools to further comprehend the complexity of lipoprotein metabolism and function. The results are important in order to improve our understanding of HDL in CVD and to explain an increased risk of CVD associated with exposure to organic pollutants.

    Delarbeid
    1. ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
    Åpne denne publikasjonen i ny fane eller vindu >>ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
    Vise andre…
    2014 (engelsk)Inngår i: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 8, nr 3-4, s. 241-250Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    PURPOSE: Mutations in apolipoprotein A-I (apoA-I) may affect plasma high-density lipoprotein (HDL) cholesterol levels and the risk for cardiovascular disease but little is known about the presence and effects of circulating apoA-I variants. This study investigates whether the apoA-I mutations, apoA-I(L202P) and apoA-I(K131del) , are present on plasma HDL particles derived from heterozygote carriers and whether this is associated to changes in HDL protein composition.

    EXPERIMENTAL DESIGN: Plasma HDL of heterozygotes for either apoA-I(L202P) or apoA-I(K131del) and family controls was isolated using ultracentrifugation. HDL proteins were separated by 2DE and analyzed by MS.

    RESULTS: ApoA-I peptides containing apoA-I(L202P) or apoA-I(K131del) were identified in HDL from heterozygotes. The apoA-I(L202P) mutant peptide was less abundant than wild-type peptide while the apoA-I(K131del) mutant peptide was more abundant than wild-type peptide in the heterozygotes. Two-dimensional gel electrophoresis analyses indicated that, compared to controls, HDL in apoA-I(L202P) carriers contained less apoE and more zinc-α-2-glycoprotein while HDL from the apoA-I(K131del) heterozygotes contained more alpha-1-antitrypsin and transthyretin.

    CONCLUSIONS AND CLINICAL RELEVANCE: Both apoA-I(L202P) and apoA-I(K131del) were identified in HDL. In heterozygotes, these mutations have markedly differential effects on the concentration of wild-type apoA-I in the circulation, as well as the HDL proteome, both of which might affect the clinical phenotype encountered in the heterozygous carriers.

    sted, utgiver, år, opplag, sider
    Wiley-Blackwell, 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-105992 (URN)10.1002/prca.201300014 (DOI)000334251600013 ()24273187 (PubMedID)
    Tilgjengelig fra: 2014-04-16 Laget: 2014-04-16 Sist oppdatert: 2018-01-11
    2. Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
    Åpne denne publikasjonen i ny fane eller vindu >>Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
    Vise andre…
    2015 (engelsk)Inngår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1851, nr 12, s. 1587-1595Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1P297S mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1P297S heterozygotes.

    Lipoproteins from six SR-B1P297S carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed.

    Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I.

    The SR-B1P297S mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.

    sted, utgiver, år, opplag, sider
    Elsevier, 2015
    Emneord
    ApoE; ApoL-1; HDL; LDL/VLDL; P297S; SR-B1
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-122723 (URN)10.1016/j.bbalip.2015.09.006 (DOI)000364252800008 ()26454245 (PubMedID)
    Merknad

    Funding agencies: EUs Sixth Framework Program [037631]; European Union [FP7-603091-2]; CardioVascular Research Initiative [CVON2011-16]; Research Council of South East Sweden [FORSS-3755]; County Council of Ostergotland (C-ALF); Faculty of Health Sciences in Linkoping; Ven

    Tilgjengelig fra: 2015-11-18 Laget: 2015-11-18 Sist oppdatert: 2018-05-27
    3. Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
    Åpne denne publikasjonen i ny fane eller vindu >>Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
    Vise andre…
    2014 (engelsk)Inngår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 65, s. 93-9Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Persistent organic pollutants (POPs) are lipophilic environmental toxins that have been associated with cardiovascular disease (CVD) and cancer. The aim of this study was to investigate the concentrations of POPs in human high and low/very low-density lipoproteins (HDL and LDL/VLDL) and the possible association with CVD and cancer occurrence in individuals living in a contaminated area. Lipoproteins from 28 individuals (7 healthy controls, 8 subjects with cancer, 13 subjects with CVD) were isolated and the fraction-specific concentration of 20 different POPs was analyzed by high resolution gas chromatography/high resolution mass spectrometry. The activity of Paraoxonase 1 (PON1), an anti-oxidant in HDL, was determined in plasma of these 28 subjects and additional 50 subjects from the same area excluding diseases other than cancer or CVD. Fourteen polychlorinated biphenyls (PCBs) and three organochlorine pesticides were detected, and especially highly chlorinated PCBs were enriched in lipoproteins. Significantly higher concentrations of POPs were found among individuals with CVD or cancer compared to controls. Principal component analyses showed that POP concentrations in HDL were more associated with CVD, while POP concentrations in LDL/VLDL were more associated with cancer. PON1 activity was negatively correlated to sumPCB and a co-variation between decreased arylesterase-activity, increased PCB concentrations and CVD was found. This study shows that POPs are present in lipoproteins and were more abundant in individuals with CVD or cancer compared to healthy controls. The results also indicate that PCB exposure is accompanied by reduced PON1 activity that could impair the HDL function to protect against oxidation.

    sted, utgiver, år, opplag, sider
    Elsevier, 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-104755 (URN)10.1016/j.envint.2013.12.017 (DOI)000334728500010 ()24472825 (PubMedID)
    Tilgjengelig fra: 2014-02-25 Laget: 2014-02-25 Sist oppdatert: 2018-01-11
  • 66.
    Ljunggren, Stefan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Helmfrid, Ingela
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Arbets- och miljömedicin.
    Norinder, Ulf
    Swedish Toxicol Science Research Centre, Sweden.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Wingren, Gun
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Helen
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Arbets- och miljömedicin.
    Lindahl, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Alterations in high-density lipoprotein proteome and function associated with persistent organic pollutants2017Inngår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 98, s. 204-211Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is a growing body of evidence that persistent organic pollutants (POPs) may increase the risk for cardiovascular disease (CVD), but the mechanisms remain unclear. High- density lipoprotein (HDL) acts protective against CVD by different processes, andwe have earlier found that HDL from subjects with CVD contains higher levels of POPs than healthy controls. In the present study, we have expanded analyses on the same individuals living in a contaminated community and investigated the relationship between the HDL POP levels and protein composition/ function. HDL from17 subjectswas isolated by ultracentrifugation. HDL protein composition, using nanoliquid chromatography tandemmass spectrometry, and antioxidant activity were analyzed. The associations of 16 POPs, including polychlorinated biphenyls (PCBs) and organochlorine pesticides, with HDL proteins/functionswere investigated by partial least square and multiple linear regression analysis. Proteomic analyses identified 118 HDL proteins, of which ten were significantly (p b 0.05) and positively associated with the combined level of POPs or with highly chlorinated PCB congeners. Among these, cholesteryl ester transfer protein and phospholipid transfer protein, as well as the inflammatory marker serum amyloid A, were found. The serum paraoxonase/arylesterase 1 activity was inversely associated with POPs. Pathway analysis demonstrated that up- regulated proteinswere associatedwith biological processes involving lipoproteinmetabolism, while down- regulated proteinswere associatedwith processes such as negative regulation of proteinases, acute phase response, platelet degranulation, and complement activation. These results indicate an association between POP levels, especially highly chlorinated PCBs, and HDL protein alterations that may result in a less functional particle. Further studies are needed to determine causality and the importance of other environmental factors. Nevertheless, this study provides a first insight into a possible link between exposure to POPs and risk of CVD. (C) 2016 Elsevier Ltd. All rights reserved.

  • 67.
    Lundgren, Hanna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland.
    Martinsson, Klara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland.
    Cederbrant, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Södertälje, Sweden.
    Jirholt, Johan
    AstraZeneca RandD, Sweden.
    Mucs, Daniel
    Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Södertälje, Sweden.
    Madeyski-Bengtson, Katja
    AstraZeneca RandD, Sweden.
    Havarinasab, Said
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 9, artikkel-id e0184744Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immunemediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202, -DQA1*0201) were created. These two lines were crossed with a human (h) CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a preclinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.

  • 68.
    Lönnqvist, Susanna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Briheim, Kristina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Kratz, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Non-occlusive topical exposure of human skin in vitro as model for cytotoxicity testing of irritant compounds2016Inngår i: Toxicology Mechanisms and Methods, ISSN 1537-6516, E-ISSN 1537-6524, Vol. 26, nr 2, s. 82-87Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Testing of irritant compounds has traditionally been performed on animals and human volunteers. Animal testing should always be restricted and for skin irritancy mice and rabbits hold poor predictive value for irritant potential in humans. Irritant testing on human volunteers is restricted by the duration subjects can be exposed, and by the subjectivity of interpreting the visual signs of skin irritation. We propose an irritant testing system using viable human full thickness skin with the loss of cell viability in the exposed skin area as end point measurement. Skin was exposed to sodium dodecyl sulfate (SDS) at 20% concentration by non-occluded topical exposure to establish a positive control response and subsequent test compounds were statistically compared with the 20% SDS response. Cell viability and metabolism were measured with 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The model presents correlation between increased concentration of SDS and decreased viability of cells in the exposed skin area (R2 = 0.76). We propose the model to be used for cytotoxicity testing of irritant compounds. With fully intact barrier function, the model comprises all cells present in the skin with quantifiable end point measurement.

  • 69.
    Malmqvist, K.
    et al.
    Division of Internal Medicine, Karolinska Inst. Danderyd Hospital, Stockholm, Sweden.
    Öhman, K. Peter
    Linköpings universitet, Institutionen för medicin och vård, Internmedicin. Linköpings universitet, Hälsouniversitetet. AstraZeneca Research & Development, Mölndal, Sweden.
    Lind, Lars
    AstraZeneca Research and Development, Mölndal, Sweden, Department of Medical Sciences, University Hospital, Uppsala, Sweden.
    Nyström, Fredrik
    Linköpings universitet, Institutionen för medicin och vård, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Inst. Danderyd Hospital, Stockholm, Sweden, Institutet Danderyd Hospital, Section of Cardiology, Division of Internal Medicine, S-182 88 Stockholm, Sweden.
    Long-Term Effects of Irbesartan and Atenolol on the Renin-Angiotensin-Aldosterone System in Human Primary Hypertension: The Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA)2003Inngår i: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 42, nr 6, s. 719-726Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We examined long-term influence of the angiotensin II type 1-receptor blocker irbesartan and the beta1-adrenergic receptor blocker atenolol on some neurohormonal systems implicated in the pathophysiology of cardiac hypertrophy. Thus, 115 hypertensive patients with left ventricular hypertrophy were randomized to receive double-blind irbesartan or atenolol, with additional therapy if needed. Neurohormone measurements and echocardiography were performed at weeks 0, 12, 24, and 48. Left ventricular mass was reduced more by irbesartan than by atenolol (-26 g/m2 versus -14 g/m2, P = 0.024), despite similar reductions in blood pressure. Plasma renin activity and angiotensin II increased (P < 0.001) by irbesartan (0.9 ± 0.7 to 3.4 ± 4.2 ng/mL × h, and 3.0 ± 1.6 to 13.0 ± 17.7 pmol/L), but decreased (P < 0.01) by atenolol (1.0 ± 0.6 to 0.7 ± 0.6 ng/mL × h, and 3.4 ± 1.6 to 3.2 ± 2.2 pmol/L). Serum aldosterone decreased (P < 0.05) by both irbesartan (346 ± 140 to 325 ± 87 pmol/L) and atenolol (315 ± 115 to 283 ± 77 pmol/L). Changes in left ventricular mass by irbesartan related inversely to changes in plasma renin activity, angiotensin II, and aldosterone (all P < 0.05). Plasma levels and 24-hour urinary excretions of catecholamines, plasma leptin, proinsulin, insulin and insulin sensitivity remained largely unchanged in both groups. Thus, the renin-angiotensin aldosterone system appears to be an important non-hemodynamic factor in the regulation of left ventricular mass.

  • 70.
    Malmström, Rickard E.
    et al.
    Karolinska University Hospital Solna, Sweden.
    Godman, Brian B.
    Karolinska University Hospital Huddinge, Sweden; University of Liverpool, England; University of Strathclyde, Scotland.
    Diogene, Eduard
    Catalan Institute Heatlh, Spain.
    Baumgartel, Christoph
    Austrian Medical and Medical Dev Agency, Austria.
    Bennie, Marion
    University of Strathclyde, Scotland; NHS National Serv Scotland, Scotland.
    Bishop, Iain
    NHS National Serv Scotland, Scotland.
    Brzezinska, Anna
    Agency Health Technology Assessment, Poland.
    Bucsics, Anna
    Hauptverband Osterreichischen Sozialversicherung, Austria.
    Campbell, Stephen
    University of Manchester, England.
    Ferrario, Alessandra
    LSEHealth, England.
    Finlayson, Alexander E.
    Weston Educat Centre, England.
    Furst, Jurij
    Health Insurance Institute, Slovenia.
    Garuoliene, Kristina
    National Health Insurance Fund, Lithuania.
    Gomes, Miguel
    Institute Nacl Farmacia and Med, Portugal.
    Gutierrez-Ibarluzea, Inaki
    Ministry Health Basque Country, Spain.
    Haycox, Alan
    University of Liverpool, England.
    Hviding, Krystyna
    Norwegian Medical Agency, Norway.
    Herholz, Harald
    Kassenarztliche Vereinigung Hessen, Germany.
    Hoffmann, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Jan, Saira
    Horizon Blue Cross Blue Shield New Jersey, NJ USA.
    Jones, Jan
    NHS Tayside, Scotland.
    Joppi, Roberta
    Local Health Unit Verona, Italy.
    Kalaba, Marija
    Republ Institute Health Insurance, Serbia.
    Kvalheim, Christina
    Norwegian Medical Agency, Norway.
    Laius, Ott
    State Agency Med, Estonia.
    Langner, Irene
    Wissenschaftliches Institute AOK, Germany.
    Lonsdale, Julie
    Lancashire Commissioning Support Unit, England.
    Lööv, Sven-Åke
    Stockholm County Council, Sweden.
    Malinowska, Kamila
    HTA Consulting, Poland; Medical Centre Postgrad Educat, Poland.
    McCullagh, Laura
    St James Hospital, Ireland.
    Paterson, Ken
    Scottish Medical Consortium, Scotland.
    Markovic-Pekovic, Vanda
    University of Banja Luka, Bosnia and Herceg; Ministry Health and Social Welfare, Bosnia and Herceg.
    Martin, Andrew
    NHS Bury, England.
    Piessnegger, Jutta
    Hauptverband Osterreichischen Sozialversicherung, Austria.
    Selke, Gisbert
    State Agency Med, Estonia.
    Sermet, Catherine
    Institute Rech and Documentat Econ St, France.
    Simoens, Steven
    Katholieke University of Leuven, Belgium.
    Tulunay, Cankat
    President Turkish Rational Drug Use Platform, Turkey.
    Tomek, Dominik
    Comenius University, Slovakia; Slovak Medical University, Slovakia.
    Voncina, Luka
    Minist Heatlh, Croatia.
    Vlahovic-Palcevski, Vera
    University Hospital Rijeka, Croatia.
    Wale, Janet
    Independent Consumer Advocate, Australia.
    Wilcock, Michael
    Royal Cornwall Hospital NHS Trust, England.
    Wladysiuk, Magdalena
    HTA Consulting, Poland.
    van Woerkom, Menno
    Dutch Institute Rational Use Med, Netherlands.
    Zara, Corrine
    Catalan Health Serv, Spain.
    Gustafsson, Lars L.
    Karolinska University Hospital Huddinge, Sweden.
    Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs2013Inngår i: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 4, artikkel-id 39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups. Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process. Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.

  • 71.
    Martis, Mihaela-Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Tarbiat, Behdad
    Swedish University of Agriculture Science SLU, Sweden.
    Tyden, Eva
    Swedish University of Agriculture Science SLU, Sweden.
    Jansson, Desiree S.
    National Vet Institute SVA, Sweden.
    Hoglund, Johan
    Swedish University of Agriculture Science SLU, Sweden.
    RNA-Seqde novo assembly and differential transcriptome analysis of the nematode Ascaridia galli in relation to in vivo exposure to flubendazole2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 11, artikkel-id 0185182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The nematode Ascaridia galli (order Ascaridida) is an economically important intestinal parasite responsible for increased food consumption, reduced performance and elevated mortality in commercial poultry production. This roundworm is an emerging problem in several European countries on farms with laying hens, as a consequence of the recent European Union (EU) ban on conventional battery cages. As infection is associated with slow development of low levels of acquired protective immunity, parasite control relies on repeated use of dewormers (anthelmintics). Benzimidazoles (BZ) are currently the only anthelmintic registered in the EU for use in controlling A. galli and there is an obvious risk of overuse of one drug class, selecting for resistance. Thus we developed a reference transcriptome of A. galli to investigate the response in gene expression before and after exposure to the BZ drug flubendazole (FLBZ). Transcriptional variations between treated and untreated A. galli showed that transcripts annotated as mitochondrial glutamate dehydrogenase and cytochrome P450 were significantly down-regulated in treated worms, whereas transcripts homologous to heat shock proteins (HSP), catalase, phosphofructokinase, and a multidrug resistance Pglycoprotein (PGP1) were significantly up-regulated in treated worms. Investigation of candidate transcripts responsible for anthelmintic resistance in livestock nematodes led to identification of several tubulins, including six new isoforms of beta-tubulin, and several ligandgated ionotropic receptors and ABC-transporters. We discovered several transcripts associated with drug binding and processing genes, but further characterisation using a larger set of worms exposed to BZs in functional assays is required to determine how these are involved in drug binding and metabolism.

  • 72.
    Mirrasekhian, Elahe
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Nilsson, Johan L. Å.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Shionoya, Kiseko
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Blomgren, Anders
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Zygmunt, Peter M.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, S-221 85 Lund, Sweden.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Högestätt, Edward D.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1–mediated hypothermia and is associated with prostaglandin inhibition in the brain2018Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol?s propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E2 in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol?s antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E2, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.?Mirrasekhian, E., Nilsson, J. L. Å., Shionoya, K., Blomgren, A., Zygmunt, P. M., Engblom, D., Högestätt, E. D., Blomqvist, A. The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1?mediated hypothermia and is associated with prostaglandin inhibition in the brain.

  • 73.
    Motwani V, Hitesh
    et al.
    Department of Materials and Environmental Chemistry, Stockholm Unviersity, Stockholm 106 91 , Sweden.
    Qiu, Shiran
    Department of Material and Environmental Chemistry, Stockholm University, Stockholm 106 91, Sweden.
    Golding, Bernard T
    School of Chemistry, Newcastle University, United Kingdom.
    Kylin, Henrik
    Norwegian Institute for Air Research, Polar Environmental Centre, Norway.
    Törnqvist, Margareta
    Departments of Material and Environmental Chemistry, Stockholm University, Stockholm 106 91 , Sweden.
    Cob(I)alamin Reacts with Sucralose to Afford an Alkylcobalamin: Relevance to In Vivo Cobalamin and Sucralose Interaction2011Inngår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 49, nr 4, s. 750-757Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vitamin B12, viz., cyano- or hydroxo-cobalamin, can be chemically or enzymatically converted into the derivatives methyl- and adenosyl-cobalamin, which are complex organometallic cofactors associated with several cobalamin-dependent enzymes. The reduced form of vitamin B12, cob(I)alamin {Cbl(I)}, obtained by reduction of hydroxocobalamin (OH-Cbl) with e.g. sodium borohydride, is one of the most powerful nucleophiles known. Cbl(I) was shown to react readily with the synthetic sweetener sucralose (1,6-dichloro-1,6-dideoxy-β-d-fructofuranosyl-4-chloro-4-deoxy-α-d-galactopyranoside) in an aqueous system to form an alkylcobalamin (Suc-Cbl). This occurred by replacement of one of the three chlorine atoms of sucralose with a cobalamin moiety. The efficiency of trapping sucralose in presence of excess Cbl(I) was estimated to be >90%. Furthermore, in an in vitro study using human liver S9 with NADPH regeneration, in presence of OH-Cbl and sucralose, Suc-Cbl was shown to be formed. The Suc-Cbl was characterized primarily by LC-ESI+-MS/MS. Given the human consumption of sucralose from food and beverages, such a reaction between the sweetener and reduced vitamin B12 could occur in vivo.

  • 74.
    Nelson, Britta S.
    et al.
    Univ Georgia, GA 30602 USA.
    Fulenwider, Hannah D.
    Univ Georgia, GA 30602 USA.
    Nennig, Sadie E.
    Univ Georgia, GA 30602 USA.
    Smith, Britessia M.
    Univ Georgia, GA 30602 USA.
    Sequeira, Michelle K.
    Univ Georgia, GA 30602 USA.
    Chimberoff, Scott H.
    Univ Georgia, GA 30602 USA.
    Richie, Christopher T.
    NIDA, MD 20892 USA.
    Cheng, Kejun
    NIAAA, MD USA; NIDA, MD 20892 USA; US FDA, MD USA.
    Rice, Kenner C.
    NIAAA, MD USA; NIDA, MD 20892 USA.
    Harvey, Brandon K.
    NIDA, MD 20892 USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken inkl beroendekliniken.
    Schank, Jesse R.
    Univ Georgia, GA 30602 USA.
    Escalated Alcohol Self-Administration and Sensitivity to Yohimbine-lnduced Reinstatement in Alcohol Preferring Rats: Potential Role of Neurokinin-1 Receptors in the Amygdala2019Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 413, s. 77-85Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic factors significantly contribute to the risk for developing alcoholism. To study these factors and other associated phenotypes, rodent lines have been developed using selective breeding for high alcohol preference. One of these models, the alcohol preferring (P) rat, has been used in hundreds of preclinical studies over the last few decades. However, very few studies have examined relapse-like behavior in this rat strain. In this study, we used operant self-administration and yohimbine-induced reinstatement models to examine relapse-like behavior in P rats. Our previous work has demonstrated that P rats show increased expression of the neurokinin-1 receptor (NK1R) in the central nucleus of the amygdala (CeA), and this functionally contributes to escalated alcohol consumption in this strain. We hypothesized that P rats would show increased sensitivity to yohimbine-induced reinstatement that is also mediated by NK1R in the CeA. Using Fos staining, site-specific infusion of NK1R antagonist, and viral vector overexpression, we examined the influence of NK1R on the sensitivity to yohimbine-induced reinstatement of alcohol seeking. We found that P rats displayed increased sensitivity to yohimbine-induced reinstatement as well as increased neuronal activation in the CeA after yohimbine injection compared to the control Wistar strain. Intra-CeA infusion of NK1R antagonist attenuates yohimbine-induced reinstatement in P rats. Conversely, upregulation of NK1R within the CeA of Wistar rats increases alcohol consumption and sensitivity to yohimbine-induced reinstatement. These findings suggest that NK1R upregulation in the CeA contributes to multiple alcohol-related phenotypes in the P rat, including alcohol consumption and sensitivity to relapse. (C) 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 75.
    Nilsson, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Elander, Louise
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Örtegren (Kugelberg), Unn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent2017Inngår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 60, s. 27-31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1–4) that was critical for the anorexic response to peripherally injected interleukin-1β (IL-1β). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1β induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1β evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1β in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1β; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1β evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.

  • 76.
    Nilsson, Gunnel
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Influence of pre-analytical conditions on the interpretation of zopiclone concentrations in whole blood2011Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 207, nr 1-3, s. 35-39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Zopiclone is a short-acting hypnotic drug used for treatment of insomnia and its stability has been described in some detail. However, data especially on short-term pre-analytical stability is missing. This study investigated zopiclone stability differences between spiked and authentic whole blood from subjects dosed with zopiclone. In this way influence from physiological factors such as drug interactions, matrix composition and plasma protein levels were minimized. Nine volunteers participated in the study. Whole blood was obtained before and after oral administration of 10 mg Imovane®. Aliquots of 1 g of authentic and spiked blood were after initial measuring, stored at 20°C during 5 days, 5°C or -20°C during 3 months, and zopiclone was measured by gas chromatography with nitrogen phosphorus detection. The results showed no stability differences between authentic and spiked blood but confirmed the very short stability in whole blood at ambient temperature. In summary, the stability was less than 1 day at 20°C, less than 2 weeks at 5°C, but stable for 3 months at -20°C. This study demonstrates the importance of controlling pre-analytical conditions from sampling to analysis to avoid misinterpretation of toxicological results.

  • 77.
    Nilsson, Gunnel
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Quantitative Analysis of Zopiclone, N-desmethylzopiclone, Zopiclone N-oxide and 2-Amino-5-chloropyridine in Urine Using LC-MS-MS2014Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 38, nr 6, s. 327-334Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A simple LC-MS/MS method was validated to allow determination of zopiclone (ZOP), Ndesmethylzopiclone (NDZOP), zopiclone N-oxide (ZOPNO) and 2-amino-5 chloropyridine (ACP) in urine at concentrations up to 3000 ng/mL within 3.5 min. This method was used for quantitative analysis of the analytes in authentic urine samples obtained 10 h after oral administration of zopiclone (Imovane®) and in aliquots of the same urine samples after different storage conditions. Additionally, pH of each studied urine sample was measured over time. The results showed that formation of ACP occurred at elevated pH and/or temperature by degradation of ZOP, NDZOP and ZOPNO. This method was also applied to samples obtained from two female victims of drug-facilitated assault. One sample had been exposed to long-term storage conditions at different temperatures and at pH>8.2, which resulted in high concentrations of ACP. The other sample, which was exposed to pH <6.5, showed no formation of ACP. ACP is formed both from ZOP and from its metabolites NDZOP and ZOPNO depending on the pH of the urine, time of storage and/or the temperature conditions. For correct interpretation in forensic cases ZOP, its major metabolites and ACP should be analyzed. When ACP is identified in urine the concentrations of ZOP, NDZOP and ZOPNO should be interpreted with great caution.

  • 78.
    Niward, Katarina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Ek Blom, Linnea
    Karolinska Inst, Sweden.
    Davies Forsman, Lina
    Karolinska Inst, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Eliasson, Erik
    Karolinska Univ Hosp Huddinge, Sweden.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Chryssanthou, Erja
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Paues, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay2018Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, nr 5, artikkel-id e00218-18Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h post-dose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment.

  • 79.
    Nylander, Martina
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    The thrombin receptors PAR1 and PAR4 and their relative role in platelet activation2009Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Many blood cell mechanisms in the human body are working all the time to maintain haemostasis in the blood vessels. Once a wound arises platelets are alerted via different substances to cover the wound and prevent loss of blood. Most of the times these mechanisms do stop the blood, and further heal the wound. During other circumstances the platelet-covering continues to form a thrombus, preventing the blood to flow and instead causes myocardial infarction or stroke. There are several risk factors triggering development of circulatory diseases such as obesity, lack of exercise, smoking, infection and stress.

    This thesis describes the interaction between the two platelet thrombin receptors PAR1 and PAR4, together with the interaction of the oral pathogen Porphyromonas gingivalis (with thrombin-like gingipains), and the cross talk with the stress hormone epinephrine and its α2A adrenergic receptor. Until now PAR1 is thought to be the most important thrombin receptor due to its high affinity for thrombin. From a phylogenetical and patophysiological point of view there must be a reason why platelets express two different thrombin receptors. Today PAR4 is considered less important, but this thesis implies that PAR4 plays an important role in platelet signaling and haemostasis.

    The results show that bacteria pre-stimulated platelets, followed by epinephrine gives a strong and full aggregation and calcium mobilization, in both aspirinated and non-aspirinated human platelets. The amount of bacteria does not itself, or epinephrine alone give aggregation or calcium mobilization. This mechanism is dependent on both Rgp type gingipain released from P. gingivalis, and PARs in an interaction with the α2A adrenergic receptor.

    Further, results reveal that PAR4 interacts and cross talks with the platelet α2A-adrenergic receptor in aspirinated platelets. Neither of the two platelet purinergic P2Y-receptors (P2Y12 and P2Y1) contribute to this action, but the purinergic P2X1 does. In aggregation studies a low dose of PAR4 activating peptide (AP), but not PAR1-AP, followed by epinephrine results in a strong aggregation and in a calcium mobilization. ATP secretion measurements did reveal that ATP was released during epinephrine stimulation, which indicate that ATP and P2X1 have a key role in this event. By blocking P2X1 both aggregation and calcium mobilization were abolished, but not by blocking P2Y12 and P2Y1. Inhibition of PI3-kinase, both epinephrine-induced calcium mobilization and aggregation were significant reduced. In non-aspirinated platelets PAR1 synergizes with the α2A adrenergic receptor and P2X1.

    In conclusion, this thesis suggests that PAR4 plays an intriguing and important role in platelets with inactived cyclooxygenase 1.  The results described in this thesis contribute to an increased knowledge of the platelet thrombin receptors.

    Delarbeid
    1. The periodontal pathogen Porphyromonas gingivalis sensitises human blood platelets to epinephrine
    Åpne denne publikasjonen i ny fane eller vindu >>The periodontal pathogen Porphyromonas gingivalis sensitises human blood platelets to epinephrine
    2008 (engelsk)Inngår i: Platelets, ISSN 1369-1635, Vol. 19, nr 5, s. 352-358Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Recent studies indicate connections between periodontitis and atherothrombosis, and the periodontal pathogen Porphyromonas gingivalis has been found within atherosclerotic lesions. P. gingivalis-derived proteases, designated gingipains activate human platelets, probably through a "thrombin-like" activity on protease-activated receptors (PARs). However, the potential interplay between P. gingivalis and other physiological platelet activators has not been investigated. The aim of this study was to elucidate consequences and mechanisms in the interaction between P. gingivalis and the stress hormone epinephrine. By measuring changes in light transmission through platelet suspensions, we found that P. gingivalis provoked aggregation, whereas epinephrine alone never had any effect. Intriguingly, pre-treatment of platelets with a low, sub-threshold number of P. gingivalis (i.e. a density that did not directly provoke platelet aggregation) resulted in a marked aggregation response when epinephrine was added. This synergistic action was not inhibited by the cyclooxygenas inhibitor aspirin. Furthermore, fura-2-measurements revealed that epinephrine caused an intracellular Ca(2+) mobilization in P. gingivalis pre-treated platelets, whereas epinephrine alone had no effect. Inhibition of the arg-specific gingipains, but not the lys-specific gingipains, abolished the aggregation and the Ca(2+) response provoked by epinephrine. Similar results were achieved by separate blockage of platelet alpha(2)-adrenergic receptors and PARs. In conclusion, the present study shows that a sub-threshold number of P. gingivalis sensitizes platelets to epinephrine. We suggest that P. gingivalis-derived arg-specific gingipains activates a small number of PARs on the surface of the platelets. This leads to an unexpected Ca(2+) mobilization and a marked aggregation response when epinephrine subsequently binds to the alpha(2)-adrenergic receptor. The present results are consistent with a direct connection between periodontitis and stress, and describe a novel mechanism that may contribute to pathological platelet activation.

    sted, utgiver, år, opplag, sider
    Taylor & Francis, 2008
    Emneord
    Atherosclerosis, growth factors, infection, inflammation, lipoproteins
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-20725 (URN)10.1080/09537100802056102 (DOI)18791941 (PubMedID)
    Tilgjengelig fra: 2009-09-18 Laget: 2009-09-18 Sist oppdatert: 2011-10-14
    2. The ATP-gated P2X1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine
    Åpne denne publikasjonen i ny fane eller vindu >>The ATP-gated P2X1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine
    Vise andre…
    2008 (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, nr 27, s. 18493-18504Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Human platelets express protease-activated receptor 1 (PAR1) and PAR4 but limited data indicate for differences in signal transduction. We studied the involvement of PAR1 and PAR4 in the cross-talk between thrombin and epinephrine. The results show that epinephrine acted via alpha(2A)-adrenergic receptors to provoke aggregation, secretion, and Ca(2+) mobilization in aspirin-treated platelets pre-stimulated with subthreshold concentrations of thrombin. Incubating platelets with antibodies against PAR4 or the PAR4-specific inhibitor pepducin P4pal-i1 abolished the aggregation. Furthermore, platelets pre-exposed to the PAR4-activating peptide AYPGKF, but not to the PAR1-activating peptide SFLLRN, were aggregated by epinephrine, whereas both AYPGKF and SFLLRN synergized with epinephrine in the absence of aspirin. The roles of released ATP and ADP were elucidated by using antagonists of the purinergic receptors P2X(1), P2Y(1), and P2Y(12) (i.e. NF449, MRS2159, MRS2179, and cangrelor). Intriguingly, ATP, but not ADP, was required for the epinephrine/thrombin-induced aggregation. In Western blot analysis, a low concentration of AYPGKF, but not SFLLRN, stimulated phosphorylation of Akt on serine 473. Moreover, the phosphatidyl inositide 3-kinase inhibitor LY294002 antagonized the effect of epinephrine combined with thrombin or AYPGKF. Thus, in aspirin-treated platelets, PAR4, but not PAR1, interacts synergistically with alpha(2A)-adrenergic receptors, and the PI3-kinase/Akt pathway is involved in this cross-talk. Furthermore, in PAR4-pretreated platelets, epinephrine caused dense granule secretion, and subsequent signaling from the ATP-gated P2X(1)-receptor and the alpha(2A)-adrenergic receptor induced aggregation. These results suggest a new mechanism that has ATP as a key element and circumvents the action of aspirin on epinephrine-facilitated PAR4-mediated platelet activation.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-20726 (URN)10.1074/jbc.M800358200 (DOI)18480058 (PubMedID)
    Tilgjengelig fra: 2009-09-18 Laget: 2009-09-18 Sist oppdatert: 2020-01-23bibliografisk kontrollert
  • 80.
    Näslund, Matilda
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Dexametasons effekt på trombocytaggregering och syreradikalproduktion2009Independent thesis Basic level (university diploma), 10 poäng / 15 hpOppgave
    Abstract [en]

    Platelets are important for the healing of damaged blood vessels since they have an importantpart to play in the coagulation process. At the same time, the blood must be kept fluid and notcoagulate at the wrong time. Therefore there are factors that effect the aggregation of plateletsin a positive or a negative way.

    Previous investigations have shown that platelets during stirring conditions produce reactiveoxygen species (ROS) that weaken the inhibiting effect of nitric oxides (NO) on platelets andthat the drug Dexamethasone (Dex) can reduce the ROS-production.

    The aim of this project was to investigate if glucocorticoids, in this case Dexamethasone,could restore the inhibiting effect of NO on platelets and if there was any decrease in ROS-production.

    The result of the ROS-measurements showed a great variance and it was difficult to draw anyconclusions from them, but a clear decrease in ROS, as previous reported, was not shown. In the aggregation experiments the inhibiting effect of NO was observed through the drug S-nitroso-N-acetylpenicillamine (SNAP), a NO-donator.

    From the aggregation experiments, the result seemed to be that SNAP during longerincubation time lost its inhibiting effect, probably because the cells become desensitized.With superoxid dismutase (SOD), the effect of SNAP increased, both in the experiment withlonger and shorter incubation times. Dex seemed to reinforce the aggregation in relation toboth SOD and SNAP. To understand this relation further, more investigations must be done.Another interesting experiment would be to do combinations of experiments monitoring bothaggregation and ROS-production at the same time.

  • 81.
    Olsson, Anki
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Department of Health Science, Blekinge Hospital, Karlskrona, Sweden.
    Hemostatic function and inflammatory activation after weaning from cardio pulmonary bypass2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Cardiopulmonary bypass (CPB) contributes to perioperative platelet dysfunction, increased fibrinolysis and impaired coagulation, which can have an impact on postoperative bleeding. During CPB the blood is exposed to foreign surfaces leading to activation of the coagulation system and a systemic inflammatory response with complement and leukocyte activation. Anticoagulation with heparin is used to prevent immediate blood clotting within the circuit. The heparin effect is reversed with protamine sulfate after weaning from CPB. Protamine has been suggested to impair platelet function in high doses although the mechanism is incompletely understood. Platelet dysfunction can promote bleeding which can necessitate transfusion and sometimes surgical re-exploration.

    After weaning from CPB the residual blood in the heart lung machine is usually retransfused to the patient in order to reduce the need for blood transfusion. The most common technique to transfuse residual blood is to collect the blood from the CPB circuit in an infusion bag (IB). An alternative way to re-transfuse the residual blood is by chasing it through the heart lung machine with Ringers solution, the Ringer chase technique (RC).

    The aim of this thesis was to examine a possible inhibitory effect of protamine on platelet aggregation. A second aim was to evaluate different techniques for retransfusion after weaning from CPB.

    Study I and II in this thesis are focused on the protamine effect on platelet aggregation and study III and IV on the quality of the blood in relation to the two different retransfusion techniques.

    In Study I we found that platelet aggregation evaluated by impedance aggregometry was reduced by approximately 50% after in vivo protamine administration. Protamine added in vitro also reduced platelet aggregation, by itself or in combination with heparin. Study II showed that protamine induces a marked but transient decrease in platelet aggregation already at a protamine-heparin ratio of 0.7:1, which also was sufficient to reverse the heparin anticoagulation as measured by activated clotting time (ACT). No further decrease was observed when additional protamine was given within three minutes. Platelet aggregation had begun to recover 20 minutes after protamine administration.

    In study III and IV we evaluated possible differences in quality of the retransfused residual blood from the heart-lung machine depending on if it is returned to the patient by the RC-technique or by an IB. Study III focused on biochemical markers of hemostasis, coagulation and fibrinolysis. Study IV concerns biochemical markers of inflammatory activity characterizing the inflammatory response during cardiac surgery with CPB including heparin binding protein (HBP) a new marker of neutrophil activation. CPB is associated with a marked systemic inflammatory response and levels of HBP indicates a pronounced neutrophil activation as part of a systemic inflammatory process. HBP levels during CPB was much higher than previously found during severe inflammatory conditions. We also concluded that the handling of the blood after weaning from CPB reduces platelet function, activates coagulation and fibrinolysis, increases hemolysis and the inflammatory response. Retransfusion of pump blood with the RC-technique was associated with better preserved platelet function, less hemolysis, less signs of activation of coagulation and fibrinolysis and less pronounced inflammatory activity than the commonly used IB technique. In the event of cell salvage technique not being feasible, we suggest that the RC technique is preferable to the IB technique but acknowledge that the clinical importance of this finding in terms of outcomes warrants further investigation

    Delarbeid
    1. Protamine reduces whole blood platelet aggregation after cardiopulmonary bypass
    Åpne denne publikasjonen i ny fane eller vindu >>Protamine reduces whole blood platelet aggregation after cardiopulmonary bypass
    Vise andre…
    2016 (engelsk)Inngår i: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 50, nr 1, s. 58-63Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Platelet dysfunction is an important cause of postoperative bleeding after cardiac surgery. Protamine is routinely used for reversal of heparin after cardiopulmonary bypass (CBP), but may affect platelet aggregation. We assessed changes in platelet function in relation to protamine administration. Design: Platelet aggregation was analyzed by impedance aggregometry before and after protamine administration in 25 adult cardiac surgery patients. Aggregation was also studied after in vitro addition of heparin and protamine. The activators adenosine diphosphate (ADP), thrombin receptor activating peptide-6 (TRAP), arachidonic acid (AA) and collagen (COL) were used.Results: Platelet aggregation was reduced by approximately 50% after in vivo protamine administration; ADP 640 +/- 230 (AU*min, mean +/- SD) to 250 +/- 160, TRAP 939 +/- 293 to 472 +/- 260, AA 307 +/- 238 to 159 +/- 143 and COL 1022 +/- 350 to 506 +/- 238 (all p&lt;0.001). Aggregation was also reduced after in vitro addition of protamine alone with activators ADP from 518 +/- 173 to 384 +/- 157 AU*min p&lt;0.001, and AA 449 +/- 311 to 340 +/- 285 (p&lt;0.01) and protamine combined with heparin (1:1 ratio) with activators ADP to 349 +/- 160 and AA to 308 +/- 260 (both p&lt;0.001); and COL from 586 +/- 180 to 455 +/- 172 (p&lt;0.05). Conclusions: Protamine given after CPB markedly reduces platelet aggregation. Protamine added in vitro also reduces platelet aggregation, by itself or in combination with heparin.

    sted, utgiver, år, opplag, sider
    TAYLOR & FRANCIS LTD, 2016
    Emneord
    Cardiopulmonary bypass; platelet aggregation; platelet function tests; protamine
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-124094 (URN)10.3109/14017431.2015.1099720 (DOI)000365693900009 ()26402229 (PubMedID)
    Merknad

    Funding Agencies|Blekinge Institute of Technology, Karlskrona; Department of Cardiothoracic Anaesthesiology and Intensive Care, County Council of Ostergotland [LIO-284621]

    Tilgjengelig fra: 2016-01-25 Laget: 2016-01-19 Sist oppdatert: 2018-04-03
    2. Better platelet function, less fibrinolysis and less hemolysis in re-transfused residual pump blood with the Ringer's chase technique: a randomized pilot study
    Åpne denne publikasjonen i ny fane eller vindu >>Better platelet function, less fibrinolysis and less hemolysis in re-transfused residual pump blood with the Ringer's chase technique: a randomized pilot study
    Vise andre…
    2018 (engelsk)Inngår i: Perfusion, ISSN 0267-6591, E-ISSN 1477-111X, Vol. 33, nr 3, s. 185-193Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    INTRODUCTION: Residual pump blood from the cardiopulmonary bypass (CPB) circuit is often collected into an infusion bag (IB) and re-transfused. An alternative is to chase the residual blood into the circulation through the arterial cannula with Ringer's acetate. Our aim was to assess possible differences in hemostatic blood quality between these two techniques.

    METHODS: Forty adult patients undergoing elective coronary artery bypass graft surgery with CPB were randomized to receive the residual pump blood by either an IB or through the Ringer's chase (RC) technique. Platelet activation and function (impedance aggregometry), coagulation and hemolysis variables were assessed in the re-transfused blood and in the patients before, during and after surgery. Results are presented as median (25-75 quartiles).

    RESULTS: Total hemoglobin and platelet levels in the re-transfused blood were comparable with the two methods, as were soluble platelet activation markers P-selectin and soluble glycoprotein VI (GPVI). Platelet aggregation (U) in the IB blood was significantly lower compared to the RC blood, with the agonists adenosine diphosphate (ADP) 24 (10-32) vs 46 (33-65), p<0.01, thrombin receptor activating peptide (TRAP) 50 (29-73) vs 69 (51-92), p=0.04 and collagen 24 (17-28) vs 34 (26-59), p<0.01. The IB blood had higher amounts of free hemoglobin (mg/L) (1086 (891-1717) vs 591(517-646), p<0.01) and D-dimer 0.60 (0.33-0.98) vs 0.3 (0.3-0.48), p<0.01. Other coagulation variables showed no difference between the groups.

    CONCLUSIONS: The handling of blood after CPB increases hemolysis, impairs platelet function and activates coagulation and fibrinolysis. The RC technique preserved the blood better than the commonly used IB technique.

    sted, utgiver, år, opplag, sider
    Sage Publications, 2018
    Emneord
    cardiopulmonary bypass, hemostasis, methods, platelet function tests
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-144025 (URN)10.1177/0267659117733891 (DOI)000429907500003 ()28950757 (PubMedID)2-s2.0-85041931025 (Scopus ID)
    Tilgjengelig fra: 2018-01-03 Laget: 2018-01-03 Sist oppdatert: 2020-01-23
  • 82.
    Osman, Ayman
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Autophagy in Peripheral Neuropathy2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor.

    Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy.

    In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury.

    Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits.

    Delarbeid
    1. Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study
    Åpne denne publikasjonen i ny fane eller vindu >>Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study
    2015 (engelsk)Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr 3, s. 625-632Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We addressed the question of whether the autophagy pathway occurs in human peripheral nerves and whether this pathway is associated with peripheral neuropathy in diabetes mellitus. By using electron microscopy, we evaluated the presence of autophagy-related structures and neuropathy in the posterior interosseous nerve of patients who had undergone carpal tunnel release and had type 1 or type 2 diabetes mellitus, and in patients with no diabetes (controls). Autophagy-related ultrastructures were observed in the samples taken from all patients of the three groups. The number of autophagy-associated structures was significantly higher (p less than 0.05) in the nerves of patients with type 1 than type 2 diabetes. Qualitative and quantitative evaluations of fascicle area, diameter of myelinated and unmyelinated nerve fibres, the density of myelinated and unmyelinated fibres and the g-ratio of myelinated fibres were performed. We found degeneration and regeneration of a few myelinated axons in controls, and a well-developed neuropathy with the loss of large myelinated axons and the presence of many small ones in patients with diabetes. The pathology in type 1 diabetes was more extensive than in type 2 diabetes. The results of this study show that the human peripheral nerves have access to the autophagy machinery, and this pathway may be regulated differently in type 1 and type 2 diabetes; insulin, presence of extensive neuropathy, and/or other factors such as duration of diabetes and HbA(1c) level may underlie this differential regulation.

    sted, utgiver, år, opplag, sider
    Springer Verlag (Germany), 2015
    Emneord
    Autophagy; Diabetes; Electron microscopy; Human; Neuropathy; Peripheral nerve
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-115314 (URN)10.1007/s00125-014-3477-4 (DOI)000349244100024 ()25523623 (PubMedID)
    Tilgjengelig fra: 2015-03-13 Laget: 2015-03-13 Sist oppdatert: 2017-12-04
    2. Study of Autophagy and Microangiopathy in Sural Nerves of Patients with Chronic Idiopathic Axonal Polyneuropathy.
    Åpne denne publikasjonen i ny fane eller vindu >>Study of Autophagy and Microangiopathy in Sural Nerves of Patients with Chronic Idiopathic Axonal Polyneuropathy.
    Vise andre…
    2016 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 9, artikkel-id e0163427Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Twenty-five percent of polyneuropathies are idiopathic. Microangiopathy has been suggested to be a possible pathogenic cause of chronic idiopathic axonal polyneuropathy (CIAP). Dysfunction of the autophagy pathway has been implicated as a marker of neurodegeneration in the central nervous system, but the autophagy process is not explored in the peripheral nervous system. In the current study, we examined the presence of microangiopathy and autophagy-related structures in sural nerve biopsies of 10 patients with CIAP, 11 controls with inflammatory neuropathy and 10 controls without sensory polyneuropathy. We did not find any significant difference in endoneurial microangiopathic markers in patients with CIAP compared to normal controls, though we did find a correlation between basal lamina area thickness and age. Unexpectedly, we found a significantly larger basal lamina area thickness in patients with vasculitic neuropathy. Furthermore, we found a significantly higher density of endoneurial autophagy-related structures, particularly in patients with CIAP but also in patients with inflammatory neuropathy, compared to normal controls. It is unclear if the alteration in the autophagy pathway is a consequence or a cause of the neuropathy. Our results do not support the hypothesis that CIAP is primarily caused by a microangiopathic process in endoneurial blood vessels in peripheral nerves. The significantly higher density of autophagy structures in sural nerves obtained from patients with CIAP and inflammatory neuropathy vs. controls indicates the involvement of this pathway in neuropathy, particularly in CIAP, since the increase in density of autophagy-related structures was more pronounced in patients with CIAP than those with inflammatory neuropathy. To our knowledge this is the first report investigating signs of autophagy process in peripheral nerves in patients with CIAP and inflammatory neuropathy.

    sted, utgiver, år, opplag, sider
    : San Francisco, CA : Public Library of Science, 2016
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-132168 (URN)10.1371/journal.pone.0163427 (DOI)000383893500033 ()27662650 (PubMedID)
    Merknad

    Funding agencies: patient association for neurological disorders in Sweden; NeurofoErbundet(NHR-Foundation); foundation Promobilia, Sweden

    Tilgjengelig fra: 2016-10-19 Laget: 2016-10-19 Sist oppdatert: 2017-11-29bibliografisk kontrollert
  • 83.
    Palkovicova, K.
    et al.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Ihnatko, Robert
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Vadovic, P.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Betinova, E.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Skultety, L.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Frangoulidis, D.
    undeswehr Institute of Microbiology, Neuherbergstr. 11, Munich, Germany.
    Toman, R.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    A monoclonal antibody specific for a unique biomarker, virenose, in a lipopolysaccharide of Coxiella burnetii2009Inngår i: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15 Suppl 2, s. 183-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Q fever is a zoonotic disease caused by Coxiella burnetii. Easy aerosol dissemination, strong environmental persistence and high infectivity make the bacterium a serious threat for humans and animals. A rapid, sensitive and specific test for the infectious agent is still a challenge in the field. C. burnetii expresses a spectrum of amphophilic macromolecules on its surface. Among them, a lipopolysaccharide (LPS) is of particular biological, immunological and medical significance [1]. Upon serial laboratory passages in yolk sacs of embryonated hen eggs, C.

  • 84.
    Pollard, K. Michael
    et al.
    Scripps Res, CA 92037 USA.
    Cauvi, David M.
    Univ Calif San Diego, CA 92093 USA.
    Toomey, Christopher B.
    Univ Calif San Diego, CA 92093 USA.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Kono, Dwight H.
    Scripps Res, CA 92037 USA.
    Mercury-induced inflammation and autoimmunity2019Inngår i: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1863, nr 12, artikkel-id UNSP 129299Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Background: Human exposure to mercury leads to a variety of pathologies involving numerous organ systems including the immune system. A paucity of epidemiological studies and suitable diagnostic criteria, however, has hampered collection of sufficient data to support a causative role for mercury in autoimmune diseases. Nevertheless, there is evidence that mercury exposure in humans is linked to markers of inflammation and autoimmunity. This is supported by experimental animal model studies, which convincingly demonstrate the biological plausibility of mercury as a factor in the pathogenesis of autoimmune disease. Scope of the review: In this review, we focus on ability of mercury to elicit inflammatory and autoimmune responses in both humans and experimental animal models. Major conclusions: Although subtle differences exist, the inflammatory and autoimmune responses elicited by mercury exposure in humans and experimental animal models show many similarities. Proinflammatory cytokine expression, lymphoproliferation, autoantibody production, and nephropathy are common outcomes. Animal studies have revealed significant strain dependent differences in inflammation and autoimmunity suggesting genetic regulation. This has been confirmed by the requirement for individual genes as well as genome wide association studies. Importantly, many of the genes required for mercury-induced inflammation and autoimmunity are also required for idiopathic systemic autoimmunity. A notable difference is that mercury-induced autoimmunity does not require type I IFN. This observation suggests that mercury-induced autoimmunity may arise by both common and specific pathways, thereby raising the possibility of devising criteria for environmentally associated autoimmunity. General significance: Mercury exposure likely contributes to the pathogenesis of autoimmunity.

  • 85.
    Prasad, Sonal
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Hannover Med Sch, Germany.
    Ponimaskin, Evgeni
    Hannover Med Sch, Germany; Inst Cytol and Genet, Russia.
    Zeug, Andre
    Hannover Med Sch, Germany.
    Serotonin receptor oligomerization regulates cAMP-based signaling2019Inngår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 132, nr 16, artikkel-id UNSP jcs230334Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protein-protein interaction is often investigated using quantitative molecular microscopy with Forster resonant energy transfer (FRET). Here, we combined linear unmixing FRET (lux-FRET) with the simultaneous application of a FRET-based biosensor for cAMP to investigate the oligomerization between the 5-HT7 receptor (5-HT7R, also known as HTR7) and the 5-HT1A receptor (5-HT1AR, also known as HTR1A) and its importance for cAMP signaling. We found that the 5-HT7R not only stimulates cAMP production, but also forms heterooligomers with 5-HT1AR, which blocks the inhibitory effect of the latter. 5-HT7R signaling, however, is not affected by this hetero-oligomerization. By modeling the kinetics of intracellular cAMP level changes in relation to the 5-HT7R:5-HT1AR stoichiometry, we were able to decipher the complex signaling characteristics of endogenous serotonin receptors in cultured hippocampal neurons. Our findings indicate that serotonergic signaling is not only modulated by the concentration of an individual receptor but also by its specific interaction with other receptors in endogenous systems. We conclude that the regulated ratio of serotonin receptors in immature and mature neurons may be critically involved in both the onset and response to treatments of psychiatric diseases, such as anxiety and depression.

  • 86.
    Romu, Thobias
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Camilla, Vavruch
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Dahlqvist Leinhard, Olof
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Tallberg, Joakim
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Dahlström, Nils
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Östergötlands Läns Landsting, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Persson, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Östergötlands Läns Landsting, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Heglind, Mikael
    University of Gothenburg, Gothenburg, Sweden..
    Lidell, Martin
    University of Gothenburg, Gothenburg, Sweden..
    Enerbäck, Sven
    University of Gothenburg, Gothenburg, Sweden..
    Borga, Magnus
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska högskolan. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Nyström, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrinmedicinska kliniken.
    A randomized trial of cold-exposure on energy expenditure and supraclavicular brown adipose tissue volume in humans2016Inngår i: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 65, nr 6, s. 926-934Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    To study if repeated cold-exposure increases metabolic rate and/or brown adipose tissue (BAT) volume in humans when compared with avoiding to freeze.

    Design

    Randomized, open, parallel-group trial.

    Methods

    Healthy non-selected participants were randomized to achieve cold-exposure 1 hour/day, or to avoid any sense of feeling cold, for 6 weeks. Metabolic rate (MR) was measured by indirect calorimetry before and after acute cold-exposure with cold vests and ingestion of cold water. The BAT volumes in the supraclavicular region were measured with magnetic resonance imaging (MRI).

    Results

    Twenty-eight participants were recruited, 12 were allocated to controls and 16 to cold-exposure. Two participants in the cold group dropped out and one was excluded. Both the non-stimulated and the cold-stimulated MR were lowered within the group randomized to avoid cold (MR at room temperature from 1841 ± 199 kCal/24 h to 1795 ± 213 kCal/24 h, p = 0.047 cold-activated MR from 1900 ± 150 kCal/24 h to 1793 ± 215 kCal/24 h, p = 0.028). There was a trend towards increased MR at room temperature following the intervention in the cold-group (p = 0.052). The difference between MR changes by the interventions between groups was statistically significant (p = 0.008 at room temperature, p = 0.032 after cold-activation). In an on-treatment analysis after exclusion of two participants that reported ≥ 8 days without cold-exposure, supraclavicular BAT volume had increased in the cold-exposure group (from 0.0175 ± 0.015 l to 0.0216 ± 0.014 l, p = 0.049).

    Conclusions

    We found evidence for plasticity in metabolic rate by avoiding to freeze compared with cold-exposure in a randomized setting in non-selected humans.

  • 87.
    Sandgren, Per
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Berlin, Gösta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Tynngård, Nahreen
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Treatment of platelet concentrates with ultraviolet C light for pathogen reduction increases cytokine accumulation2016Inngår i: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 56, nr 6, s. 1377-1383Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUNDPathogen reduction technologies use photoactive substances in combination with ultraviolet (UV) light to inactivate pathogens. A new method uses only UVC light for pathogen reduction. This study assesses the effects of UVC light treatment on cytokine release in platelet (PLT) concentrates (PCs). STUDY DESIGN AND METHODSA PC with 35% plasma and 65% PLT additive solution (SSP+) was prepared from five buffy coats. Three such PCs were pooled and divided into 3 units. One unit was used as a nonirradiated control, the second was a gamma-irradiated control, and the third unit was treated with UVC light technology. Ten units of each type were investigated. Cytokine release was analyzed on Days 1, 5, and 7 of storage. Correlation between cytokines, PLT surface markers, and hemostatic properties was investigated. RESULTSSwirling was well preserved and pH was above the reference limit of 6.4 during storage of PLTs in all groups. Cytokine levels increased during storage in all groups but to a larger degree in PCs treated with UVC light. Only weak correlation was found between cytokines and PLT surface markers (ramp;lt;0.5). However, several cytokines showed strong correlation (ramp;gt;0.6) with the PLTs ability to promote clot retraction. CONCLUSIONUVC treatment resulted in increased release from PLT alpha granules as evident by a higher cytokine release compared to nonirradiated and gamma-irradiated PCs. The clinical relevance of these findings needs to be further evaluated.

  • 88.
    Sandin, Linnea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    The influence of lysozyme and oligothiophenes on amyloid-β toxicity in models of Alzheimer’s disease2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia worldwide. Apart from dominantly inherited mutations, age is the major risk factor and as life expectancy increases the prevalence for AD escalates dramatically. AD causes substantial problems for the affected persons and their families, and the society suffers economically. To date the available treatments only temporarily relieve the symptoms, wherefore the development of a cure is of utmost importance. The etiology of AD is still inconclusive but many believe that small aggregates (oligomers) of the protein amyloid-β (Aβ) are central for the onset of AD.

    The aims of this thesis were to investigate how different molecules affect the aggregation and toxicity of Aβ. In paper I and II, two oligothiophenes were studied; p-FTAA and h-FTAA and in paper III and IV the inflammatory protein lysozyme was explored. Differentiated neuroblastoma cells and Drosophila melanogaster were used as models of AD to address the issue.

    The results show that p-FTAA rescues neuroblastoma cells from Aβ toxicity when Aβ is coaggregated with lysozyme. Various biophysical studies show that the co-aggregation increases the formation of fibrillar Aβ structures rich in β-sheets. Noteworthy, these Aβ fibrils were more resistant to both degradation and denaturation, and less prone to propagate seeding from Aβ monomers. Furthermore, h-FTAA, but not p-FTAA, was able to protect neuroblastoma cell toxicity when exposed to Aβ with the Arctic mutation (AβArc), which probably reflects the weaker binding of AβArc to p-FTAA, compared to h-FTAA.

    Lysozyme levels were increased in CSF from patients that were both biochemically and clinically diagnosed with AD. In mice models of AD it was revealed that the mRNA increase in lysozyme correlates to increased Aβ pathology, but not to tau pathology, indicating that Aβ could drive the expression of lysozyme. To evaluate the effect for increased expression of lysozyme, co-expression of lysozyme was achieved in flies that expressed Aβ in the retina of the eyes, or in flies that expressed AβArc in the central nervous system. In all AD fly models, co-expression of lysozyme protected the cells from the Aβ induced toxicity. Of note, flies that expressed the toxic AβArc in the CNS of the flies showed an improvement in both lifespan and activity. Finally, we demonstrate that Aβ aggregating in the presence of lysozyme inhibits the cellular uptake of Aβ and also the cytotoxic effect of Aβ.

    The work included in this thesis demonstrates that the oligothiophenes p-FTAA and h-FTAA, and also lysozyme have the potential to be used as treatment strategies for sporadic AD, but remarkable, also in familial AD with the highly toxic Arctic mutation. The protective mechanism of p-FTAA seems to be attributed to the ability to generate stable Aβ fibrils with reduced seeding capacity, and that lysozyme inhibits the neuronal uptake of Aβ, which could prevent both the intracellular toxicity and cell-to-cell transmission of Aβ.

    Delarbeid
    1. The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties
    Åpne denne publikasjonen i ny fane eller vindu >>The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties
    Vise andre…
    2016 (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, nr 17, s. 9233-9243Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Aggregation of the amyloid-(beta) peptide (A beta) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the A beta peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the A beta fibrillation pathway may be a valid approach to reduce A beta cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic A beta species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting A beta-mediated cytotoxicity. Moreover, p-FTAA bound to early formed A beta species and induced a rapid formation of beta-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable A beta species that were nontoxic which indicates that p-FTAA might have therapeutic potential.

    sted, utgiver, år, opplag, sider
    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2016
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-128747 (URN)10.1074/jbc.M115.696229 (DOI)000374849000033 ()26907684 (PubMedID)
    Merknad

    Funding Agencies|Swedish Research Council; Torsten Soderberg Foundation; Alzheimer Foundation; Dementia Foundation; Linkoping University Neurobiology Center

    Tilgjengelig fra: 2016-05-31 Laget: 2016-05-30 Sist oppdatert: 2018-03-20
    2. Beneficial effects of increased lysozyme levels in Alzheimer’s disease modelled in Drosophila melanogaster
    Åpne denne publikasjonen i ny fane eller vindu >>Beneficial effects of increased lysozyme levels in Alzheimer’s disease modelled in Drosophila melanogaster
    Vise andre…
    2016 (engelsk)Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 283, nr 19, s. 3508-3522Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Genetic polymorphisms of immune genes that associate with higher risk to develop Alzheimer’s disease (AD) have led to an increased research interest on the involvement of the immune system in AD pathogenesis. A link between amyloid pathology and immune gene expression was suggested in a genome-wide gene expression study of transgenic amyloid mouse models. In this study, the gene expression of lysozyme, a major player in the innate immune system, was found to be increased in a comparable pattern as the amyloid pathology developed in transgenic mouse models of AD. A similar pattern was seen at protein levels of lysozyme in human AD brain and CSF, but this lysozyme pattern was not seen in a tau transgenic mouse model. Lysozyme was demonstrated to be beneficial for different Drosophila melanogaster models of AD. In flies that expressed Aβ1-42 or AβPP together with BACE1 in the eyes, the rough eye phenotype indicative of toxicity was completely rescued by coexpression of lysozyme. In Drosophila flies bearing the Aβ1-42 variant with the Arctic gene mutation, lysozyme increased the fly survival and decreased locomotor dysfunction dose dependently. An interaction between lysozyme and Aβ1-42 in the Drosophila eye was discovered. We propose that the increased levels of lysozyme, seen in mouse models of AD and in human AD cases, were triggered by Aβ1-42 and caused a beneficial effect by binding of lysozyme to toxic species of Aβ1-42, which prevented these from exerting their toxic effects. These results emphasize the possibility of lysozyme as biomarker and therapeutic target for AD.

    sted, utgiver, år, opplag, sider
    John Wiley & Sons, 2016
    Emneord
    Alzheimer’s disease, amyloid-β, Drosophila, lysozyme
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-131796 (URN)10.1111/febs.13830 (DOI)000386033700001 ()27562772 (PubMedID)
    Tilgjengelig fra: 2016-10-07 Laget: 2016-10-07 Sist oppdatert: 2018-03-20bibliografisk kontrollert
  • 89.
    Schank, Jesse R.
    et al.
    University of Georgia, GA 30602 USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Substance P and the Neurokinin-1 Receptor: The New CRF2017Inngår i: ROLE OF NEUROPEPTIDES IN ADDICTION AND DISORDERS OF EXCESSIVE CONSUMPTION, ISSN 0074-7742, Vol. 136, s. 151-175Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Substance P (SP) is an 11-amino acid neuropeptide of the tachykinin family that preferentially activates the neurokinin-1 receptor (NK1R). First isolated 85 years ago and sequenced 40 years later, SP has been extensively studied. Early studies identified a role for SP and the NK1R in contraction of intestinal smooth muscle, central pain processing, and neurogenic inflammation. An FDA-approved NK1R antagonist, aprepitant, is used clinically for the treatment of chemotherapy-induced nausea, as the NK1R influences the activity of the brain stem emesis centers. More recently, SP and the NK1R have gained attention for their role in complex psychiatric processes including stress, anxiety, and depression. However, clinical development of NK1R antagonists for these indications has so far been unsuccessful. Several preclinical studies have also demonstrated a role of the NK1R in drug taking and drug seeking, especially as it relates to escalated consumption and stress-elicited seeking. This line of research developed in parallel with findings supporting a role of corticotropin-releasing factor (CRF) in stress-induced drug seeking. Over this time, CRF arguably gained more attention as a target for development of addiction pharmacotherapies. However, this effort has not resulted in a viable drug for use in human populations. Given promising clinical findings for the efficacy of NK1R antagonists on craving in alcoholics, along with recent data suggesting that a number of negative results from NK1R trials were likely due to insufficient receptor occupancy, the NK1R merits being revisited as a target for the development of novel pharmacotherapeutics for addiction.

  • 90.
    Schwandt, Melanie L.
    et al.
    NIAAA, MD USA.
    Cortes, Carlos R.
    Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. NIAAA, MD USA.
    Kwako, Laura E.
    NIAAA, MD USA.
    George, David T.
    NIAAA, MD USA.
    Momenan, Reza
    NIAAA, MD USA.
    Sinha, Rajita
    Yale University, CT 06520 USA.
    Grigoriadis, Dimitri E.
    Neurocrine Bioscience, CA USA.
    Merlo Pich, Emilio
    Imperial Coll London, England.
    Leggio, Lorenzo
    NIAAA, MD USA; NIDA, MD 20892 USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken. NIAAA, MD USA.
    The CRFI Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects2016Inngår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, nr 12, s. 2818-2829Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Blockade of corticotropin-releasing factor receptor I (CRFI) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRFI antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n = 39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRFI antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRFI antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRFI blockade in stress-induced alcohol craving and relapse.

  • 91.
    Schwendener, Nicole
    et al.
    University of Bern, Switzerland.
    Jackowski, Christian
    University of Bern, Switzerland.
    Schuster, Frederick
    University of Bern, Switzerland.
    Persson, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Warntjes, Marcel Jan Bertus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Zech, Wolf-Dieter
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. University of Bern, Switzerland.
    Temperature-corrected post-mortem 1.5 T MRI quantification of non-pathologic upper abdominal organs2017Inngår i: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 131, nr 5, s. 1369-1376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study aimed to evaluate if simultaneous temperature-corrected T1, T2, and proton density (PD) 1.5 T post-mortem MR quantification [quantitative post-mortem magnetic resonance imaging (QPMMRI)] is feasible for characterizing and discerning non-pathologic upper abdominal organs (liver, spleen, pancreas, kidney) with regard to varying body temperatures. QPMMRI was performed on 80 corpses (25 females, 55 males; mean age 56.2 years, SD 17.2) prior to autopsy. Core body temperature was measured during QPMMRI. Quantitative T1, T2, and PD values were measured in the liver, pancreas, spleen, and left kidney and temperature corrected to 37 A degrees C. Histologic examinations were conducted on each measured organ to determine non-pathologic organs. Quantitative T1, T2, and PD values of non-pathologic organs were ANOVA tested against values of other non-pathologic organ types. Based on temperature-corrected quantitative T1, T2, and PD values, ANOVA testing verified significant differences between the non-pathologic liver, spleen, pancreas, and left kidneys. Temperature-corrected 1.5 T QPMMRI based on T1, T2, and PD values may be feasible for characterization and differentiation of the non-pathologic liver, spleen, pancreas, and kidney. The results may provide a base for future specific pathology diagnosis of upper abdominal organs in post-mortem imaging.

  • 92.
    Seldén, Tor
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Roman, Markus
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Druid, Henrik
    National Board of Forensic Medicine, Department of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    LC-MS-MS analysis of buprenorphine and norbuprenorphine in whole blood from suspected drug users2011Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 209, nr 1-3, s. 113-119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A liquid chromatography tandem mass spectrometry method is described for the analysis of buprenorphine and norbuprenorphine in whole blood. Linearity was achieved between 0.2-5 ng/g for buprenorphine and 0.5-5 ng/g for norbuprenorphine. Stability studies on spiked whole blood and an authentic sample showed no degradation of buprenorphine- and norbuprenorphine-glucuronide to their respective aglycones. Buprenorphine and norbuprenorphine showed some degradation when stored at 4 degrees C for three weeks, but was stable when stored at -20 degrees C for 4 weeks. The method was applied to forensic cases of driving under the influence of drugs (DUID) and petty drug offences (PDO) during 2007-2009. Out of 2459 cases analyzed, 322 were positive for both buprenorphine and norbuprenorphine (13%), 219 for buprenorphine only (9%), and 12 for norbuprenorphine only (0.5%). The mean and median concentrations (N = 322) were 1.7 and 1.0 ng/g, respectively, for buprenorphine and norbuprenorphine. The mean and median norbuprenorphine/buprenorphine ratios were 1.5 and 1.1, respectively. There was no significant difference in concentration ratios for DUID and PDO cases (p andgt; 0.05). We conclude that the described method for analysis of buprenorphine and norbuprenorphine in whole blood could be used to investigate use or misuse of buprenorphine but that many of the cases presented with very low concentrations of buprenorphine. We also conclude that analysis should be performed within two weeks unless samples are stored frozen prior to analysis.

  • 93.
    Shoeb, Mohammad
    et al.
    University of Dhaka, Bangladesh.
    Mondal, Prithu
    University of Dhaka, Bangladesh.
    Kylin, Henrik
    Linköpings universitet, Institutionen för tema, Tema Miljöförändring. Linköpings universitet, Filosofiska fakulteten.
    Nahar, Nilufar
    University of Dhaka, Bangladesh.
    Chemical and biological activity of mushrooms naturally occurring in Bangladesh2017Inngår i: Asian Journal of Pharmacognosy, E-ISSN 0128-1119, Vol. 1, nr 3, s. 42-51Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Five freeze-dried mushroom species namely Agaricus bisporus, Coprinus micaceus, Pleurotus ostreatus, Termitomyces clypeatus and T. heimii were extracted separately with dichloromethane:methanol followed by partitioned using hexane, dichloromethane and methanol. Silica gel column chromatography of hexane extract of T. heimii and dichloromethane extract of P. ostreatus afforded 2,4-di-hydroxy-9-octadecenoic acid and 2-hydroxy-9-octadecenoic acid, respectively. The n-hexane extracts of mushrooms were analyzed for the presence of n-alkanes and fatty acid compositions. n-Alkanes were found in T. heimii only. Different extracts of mushrooms were evaluated for antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria and fungi, general toxicity and antioxidant activity.

  • 94.
    Stehr, Jan Eric
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Ytors Fysik och Kemi. Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska fakulteten.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten.
    Karlsson, Jan Olof G.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Evidence that fodipir (DPDP) binds neurotoxic Pt2+ with a high affinity: An electron paramagnetic resonance study2019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 15813Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxaliplatin typically causes acute neuropathic problems, which may, in a dose-dependent manner, develop into a chronic form of chemotherapy-induced peripheral neuropathy (CIPN), which is associated with retention of Pt2+ in the dorsal root ganglion. A clinical study by Coriat and co-workers suggests that co-treatment with mangafodipir [Manganese(II) DiPyridoxyl DiPhosphate; MnDPDP] cures ongoing CIPN. These authors anticipated that it is the manganese superoxide dismutase mimetic activity of MnDPDP that explains its curative activity. However, this is questionable from a pharmacokinetic perspective. Another, but until recently undisclosed possibility is that Pt2+ outcompetes Mn2+/Ca2+/Zn2+ for binding to DPDP or its dephosphorylated metabolite PLED (diPyridoxyL EthylDiamine) and transforms toxic Pt2+ into a non-toxic complex, which can be readily excreted from the body. We have used electron paramagnetic resonance guided competition experiments between MnDPDP (10logKML ≈ 15) and K2PtCl4, and between MnDPDP and ZnCl2 (10logKML ≈ 19), respectively, in order to obtain an estimate the 10logKML of PtDPDP. Optical absorption spectroscopy revealed a unique absorption line at 255 nm for PtDPDP. The experimental data suggest that PtDPDP has a higher formation constant than that of ZnDPDP, i.e., higher than 19. The present results suggest that DPDP/PLED has a high enough affinity for Pt2+ acting as an efficacious drug in chronic Pt2+-associated CIPN.

  • 95.
    Stroikin, Yuri
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Mild, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Uno
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Lysosome-targeted stress reveals increased stability of lipofuscin-containing lysosomes2008Inngår i: Age (Omaha), ISSN 0161-9152, E-ISSN 1574-4647, Vol. 30, nr 1, s. 31-42Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cellular ageing is associated with accumulation of undegradable intralysosomal material, called lipofuscin. In order to accelerate the lipofuscin-accumulation, confluent, growth arrested human fibroblasts were cultured under hyperoxic conditions. To provide a better insight into the effects of lipofuscin on cellular functions, we compared lysosomal stability in control and lipofuscin-loaded human fibroblasts under conditions of lysosome-targeted stress induced by exposure to either the lysosomotropic detergent MSDH or the redox-cycling quinone naphthazarin. We show that lysosomal damage, assessed by acridine-orange relocation, translocation of cathepsin D to the cytosol, and alkalinization of lysosomes is more pronounced in control than in lipofuscin-loaded fibroblasts. Finding that lysosomal integrity was less affected or even preserved in case of lipofuscin-loaded cells enables us to suggest that lipofuscin exerts lysosome-stabilizing properties.

  • 96.
    Södergren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Formation and Relevance of Platelet Subpopulations2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Platelets are important players in the hemostatic system, acting as guardians of vessel integrity. When they come across a breach in the vessel wall, they quickly adhere to the damaged surface, secrete activating and adhesive compounds from their secretory granules, recruit additional platelets into a growing platelet plug and support the action of the coagulation system. In the past decades, it has become clear that platelets form functionally different platelet subpopulations. The aggregatory platelets build the platelet plug, whereas the procoagulant subpopulation support and direct the actions of the coagulation system. The aim of this thesis was to examine the formation and features of the different platelet subpopulations, and elucidate their respective roles in hemostasis.

    Platelet lysosomal secretion is not well characterized. In Paper I, we found that lysosomal secretion, detected as LAMP-1 surface exposure, occur upon potent platelet stimulation including secondary activation by ADP. This is regulated by the endothelial platelet inhibitors nitric oxide and prostacyclin. As observed in Paper II, lysosomal secretion might also be of clinical relevance as a quality indicator for platelet concentrates used for transfusion, an area were quality control may become increasingly important in the future. Among several evaluated platelet activation markers, platelet LAMP-1 exposure and the ability to form procoagulant platelets may be useful as novel indicators of platelet responsiveness. Moreover, the ability to form procoagulant platelets varies extensively between individuals, something we established in Paper III. Here we also present a novel flow cytometry protocol enabling the simultaneous investigation of 6 different platelet activation markers. Using this protocol we investigate the formation of procoagulant platelets and reveal that only a subpopulation of platelets may become procoagulant. Further we show that this is dependent on the agonist stimulation applied. Finally in Paper IV, we explore the influence of the procoagulant platelet subpopulation on different aspects of hemostasis. While platelet aggregation was not affected, the fraction of procoagulant platelets was found to strongly correlate to peak thrombin generation, and to be associated with plasma cholesterol levels.

    In conclusion, this thesis presents evidence for the use of LAMP-1 surface exposure and the formation of a procoagulant platelet subpopulation as potential indicators of platelet activation potential. The formation of procoagulant platelets varies extensively between individuals, influence hemostasis and is associated with the known risk factor cholesterol. Thus, the formation of a procoagulant platelet subpopulation may be a candidate biomarker for cardiovascular disease, to be explored in the future.

    Delarbeid
    1. Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances
    Åpne denne publikasjonen i ny fane eller vindu >>Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances
    Vise andre…
    2016 (engelsk)Inngår i: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 27, nr 1, s. 86-92Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Exocytosis of lysosomal contents from platelets has been speculated to participate in clearance of thrombi and vessel wall remodelling. The mechanisms that regulate lysosomal exocytosis in platelets are, however, still unclear. The aim of this study was to identify the pathways underlying platelet lysosomal secretion and elucidate how this process is controlled by platelet inhibitors. We found that high concentrations of thrombin induced partial lysosomal exocytosis as assessed by analysis of the activity of released N-acetyl--glucosaminidase (NAG) and by identifying the fraction of platelets exposing the lysosomal-associated membrane protein (LAMP)-1 on the cell surface by flow cytometry. Stimulation of thrombin receptors PAR1 or PAR4 with specific peptides was equally effective in inducing LAMP-1 surface expression. Notably, lysosomal exocytosis in response to thrombin was significantly reduced if the secondary activation by ADP was inhibited by the P2Y(12) antagonist cangrelor, while inhibition of thromboxane A(2) formation by treatment with acetylsalicylic acid was of minor importance in this regard. Moreover, the NO-releasing drug S-nitroso-N-acetyl penicillamine (SNAP) or the cyclic AMP-elevating eicosanoid prostaglandin I-2 (PGI(2)) significantly suppressed lysosomal exocytosis. We conclude that platelet inhibitors that mimic functional endothelium such as PGI(2) or NO efficiently counteract lysosomal exocytosis. Furthermore, we suggest that secondary release of ADP and concomitant signaling via PAR1/4- and P2Y(12) receptors is important for efficient platelet lysosomal exocytosis by thrombin.

    sted, utgiver, år, opplag, sider
    TAYLOR & FRANCIS INC, 2016
    Emneord
    ADP receptors; endothelium; exocytosis; lysosome; platelet physiology; protease activated receptors (PAR); thrombin
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-125318 (URN)10.3109/09537104.2015.1042446 (DOI)000368717700011 ()25970449 (PubMedID)
    Merknad

    Funding Agencies|County Council of Ostergotland; Swedish Research Council

    Tilgjengelig fra: 2016-02-24 Laget: 2016-02-19 Sist oppdatert: 2020-01-23
    2. Responsiveness of platelets during storage studied with flow cytometry - formation of platelet subpopulations and LAMP-1 as new markers for the platelet storage lesion
    Åpne denne publikasjonen i ny fane eller vindu >>Responsiveness of platelets during storage studied with flow cytometry - formation of platelet subpopulations and LAMP-1 as new markers for the platelet storage lesion
    2016 (engelsk)Inngår i: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 110, nr 2, s. 116-125Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background and ObjectivesStorage lesions may prevent transfused platelets to respond to agonists and arrest bleeding. The aim of this study was to evaluate and quantify the capacity of platelet activation during storage using flow cytometry and new markers of platelet activation. Materials and MethodsActivation responses of platelets prepared by apheresis were measured on days 1, 5, 7 and 12. In addition, comparisons were made for platelet concentrates stored until swirling was affected. Lysosome-associated membrane protein-1 (LAMP-1), P-selectin and phosphatidylserine (PS) exposure were assessed by flow cytometry on platelets in different subpopulations in resting state or following stimulation with platelet agonists (cross-linked collagen-related peptide (CRP-XL), PAR1- and PAR4-activating peptides). ResultsThe ability to form subpopulations upon activation was significantly decreased already at day 5 for some agonist combinations. The agonist-induced exposure of PS and LAMP-1 also gradually decreased with time. Spontaneous exposure of P-selectin and PS increased with time, while spontaneous LAMP-1 exposure was unchanged. In addition, agonist-induced LAMP-1 expression clearly discriminated platelet concentrates with reduced swirling from those with retained swirling. This suggests that LAMP-1 could be a good marker to capture changes in activation capacity in stored platelets. ConclusionThe platelet activation potential seen as LAMP-1 exposure and fragmentation into platelet subpopulations is potential sensitive markers for the platelet storage lesion.

    sted, utgiver, år, opplag, sider
    WILEY-BLACKWELL, 2016
    Emneord
    apheresis; haemostasis; platelet concentrates; platelet function; platelet transfusion
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-126141 (URN)10.1111/vox.12324 (DOI)000370657500002 ()26389538 (PubMedID)
    Merknad

    Funding Agencies|Region Ostergotland; Linkoping University through the LiU Research Fellows program

    Tilgjengelig fra: 2016-03-15 Laget: 2016-03-15 Sist oppdatert: 2020-01-23
    3. Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol
    Åpne denne publikasjonen i ny fane eller vindu >>Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol
    2018 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 1441Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    It is recognised that platelets respond differently to activation, where a subpopulation of platelets adopt a procoagulant phenotype while others are aggregatory. However, it has not been thoroughly tested whether these subpopulations will remain in maximally activated samples, or if they are merely a result of different platelet sensitivities to agonist activation. Here platelets were activated with gradually increasing concentrations of thrombin and/or the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Platelet activation was investigated using a novel six-colour flow cytometry protocol evaluating exposure of phosphatidylserine, active conformation of the fibrinogen receptor alpha(IIb)beta(3), alpha-granule and lysosomal release (P-selectin and LAMP-1 exposure), mitochondrial membrane integrity and platelet fragmentation. Upon activation by CRP-XL or thrombin+CRP-XL, platelets formed three differently sized subpopulations. Normal-sized platelets showed high exposure of aggregatory active alpha(IIb)beta(3) and intact mitochondria, while the smaller platelets and platelet fragments showed high exposure of procoagulant phosphatidylserine. The distribution of platelets between the differently sized subpopulations remained stable despite high agonist concentrations. All three were still present after 30 and 60 min of activation, showing that all platelets will not have the same characteristics even after maximal stimulation. This suggests that platelet subpopulations with distinct activation patterns exist within the total platelet population.

    sted, utgiver, år, opplag, sider
    NATURE PUBLISHING GROUP, 2018
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-145133 (URN)10.1038/s41598-017-19126-8 (DOI)000423045400014 ()29362366 (PubMedID)
    Merknad

    Funding Agencies|LiU Fund of U and Linkoping University

    Tilgjengelig fra: 2018-02-13 Laget: 2018-02-13 Sist oppdatert: 2020-01-23
  • 97.
    Södergren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Orebro Univ, Sweden.
    Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 1441Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is recognised that platelets respond differently to activation, where a subpopulation of platelets adopt a procoagulant phenotype while others are aggregatory. However, it has not been thoroughly tested whether these subpopulations will remain in maximally activated samples, or if they are merely a result of different platelet sensitivities to agonist activation. Here platelets were activated with gradually increasing concentrations of thrombin and/or the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Platelet activation was investigated using a novel six-colour flow cytometry protocol evaluating exposure of phosphatidylserine, active conformation of the fibrinogen receptor alpha(IIb)beta(3), alpha-granule and lysosomal release (P-selectin and LAMP-1 exposure), mitochondrial membrane integrity and platelet fragmentation. Upon activation by CRP-XL or thrombin+CRP-XL, platelets formed three differently sized subpopulations. Normal-sized platelets showed high exposure of aggregatory active alpha(IIb)beta(3) and intact mitochondria, while the smaller platelets and platelet fragments showed high exposure of procoagulant phosphatidylserine. The distribution of platelets between the differently sized subpopulations remained stable despite high agonist concentrations. All three were still present after 30 and 60 min of activation, showing that all platelets will not have the same characteristics even after maximal stimulation. This suggests that platelet subpopulations with distinct activation patterns exist within the total platelet population.

  • 98.
    Tien Viet Dung, Vu
    et al.
    Univ Oxford, Vietnam.
    Thi Thuy Nga, Do
    Univ Oxford, Vietnam.
    Rydell, Ulf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Nilsson, Lennart E
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Olson, Linus
    Karolinska Inst, Sweden; Training and Res Acad Collaborat Sweden Viet Nam, Vietnam.
    Larsson, Mattias
    Univ Oxford, Vietnam; Karolinska Inst, Sweden; Training and Res Acad Collaborat Sweden Viet Nam, Vietnam.
    Hanberger, Håkan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland. Training and Res Acad Collaborat Sweden Viet Nam, Vietnam.
    Choisy, Marc
    Univ Oxford, Vietnam; French Natl Res Inst Sustainable Dev, France; French Natl Ctr Sci Res, France; Univ Montpellier, France.
    Tuyet Trinh, Dao
    Natl Hosp Trop Dis, Vietnam.
    van Doorn, H. Rogier
    Univ Oxford, Vietnam.
    Van Kinh, Nguyen
    Natl Hosp Trop Dis, Vietnam.
    Vu Trung, Nguyen
    Natl Hosp Trop Dis, Vietnam.
    Wertheim, Heiman F. L.
    Univ Oxford, Vietnam; Radboudumc, Netherlands; Radboudumc, Netherlands.
    Antimicrobial susceptibility testing and antibiotic consumption results from 16 hospitals in Viet Nam: The VINARES project 2012-20132019Inngår i: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 18, s. 269-278Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To establish a hospital-based surveillance network with national coverage for antimicrobial resistance (AMR) and antibiotic consumption in Viet Nam. Methods: A 16-hospital network (Viet Nam Resistance: VINARES) was established and consisted of national and provincial-level hospitals across the country. Antimicrobial susceptibility testing results from routine clinical diagnostic specimens and antibiotic consumption data in Defined Daily Dose per 1000 bed days (DDD/1000 patient-days) were prospectively collected and analysed between October 2012 and September 2013. Results: Data from a total of 24 732 de-duplicated clinical isolates were reported. The most common bacteria were: Escherichia coli (4437 isolates, 18%), Klebsiella spp. (3290 isolates, 13%) and Acinetobacter spp. (2895 isolates, 12%). The hospital average antibiotic consumption was 918 DDD/1000 patient-days. Third-generation cephalosporins were the most frequently used antibiotic class (223 DDD/1000 patient-days, 24%), followed by fluoroquinolones (151 DDD/1000 patient-days, 16%) and second-generation cephalosporins (112 DDD/1000 patient-days, 12%). Proportions of antibiotic resistance were high: 1098/1580 (69%) Staphylococcus aureus isolates were methicillin-resistant (MRSA); 115/344 isolates (33%) and 90/358 (25%) Streptococcus pneumoniae had reduced susceptibility to penicillin and ceftriaxone, respectively. A total of 180/2977 (6%) E. coli and 242/1526 (16%) Klebsiella pneumoniae were resistant to imipenem, respectively; 602/1826 (33%) Pseudomonas aeruginosa were resistant to ceftazidime and 578/1765 (33%) to imipenem. Of Acinetobacter spp. 1495/2138 (70%) were resistant to carbapenems and 2/333 (1%) to colistin. Conclusions: These data are valuable in providing a baseline for AMR among common bacterial pathogens in Vietnamese hospitals and to assess the impact of interventions. (C) 2019 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.

  • 99.
    Toll, Johan B
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Andersson, Rolf G
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Effects of enprofylline and theophylline on purified human basophils1984Inngår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 39, nr 7, s. 515-520Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extracts from purified human basophils revealed activity of cAMP-phosphodiesterase with a km-value of 0.59 microM. The enzyme was not activated by Ca-ions. Enprofylline and theophylline inhibited the enzyme in a competitive manner. Enprofylline was more potent than theophylline. These drugs did also inhibit the anti-IgE-induced histamine release from the basophils. These results favour the hypothesis that inhibition of histamine release of enprofylline is caused by an inhibition of phosphodiesterase. Although accumulating data have indicated that theophylline, at therapeutic concentrations, is a weak inhibitor of cAMP-phosphodiesterase activity, there is reason to believe that enprofylline, at therapeutic concentrations, may act at least partly as a phosphodiesterase inhibitor.

  • 100.
    Toll, Johan B
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Andersson, Rolf G
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Effects of mepacrine and p-bromophenacyl bromide on anti-IgE and phospholipase A2-induced histamine release from human basophils1986Inngår i: Agents and actions, ISSN 0065-4299, Vol. 18, nr 5-6, s. 518-523Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Exposure of human basophils to purified phospholipase A2 caused a release of histamine, the process could be divided in one Ca2+-independent and one Ca2+-dependent stage. Low concentrations of mepacrine and p-bromophenacyl bromide (BPB) inhibited both phospholipase A2- and anti-IgE-induced histamine release. Mepacrine was more potent than BPB when the two-stage-method was used. The inhibition of mepacrine was most effective when the drug was added in the second Ca2+-dependent stage. The effect of mepacrine in the whole reaction of the anti-IgE-induced histamine release was biphasic and mepacrine was less effective than in the inhibition of the separated stages. The effect of BPB on the whole reaction was rather similar to mepacrine, although it was not biphasic. The results presented in this work confirm a previous hypothesis suggesting that activation of phospholipase A2 is an important step in the IgE-mediated histamine release process. The results also suggest that inhibition of histamine release due to inhibition of phospholipase A2 might be of therapeutical value as the system can be inhibited at very low drug concentrations.

123 51 - 100 of 117
RefereraExporteraLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf