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  • 1.
    Alfredsson, Joakim
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Lindahl, Tomas L
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Gustafsson, Kerstin M
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Janzon, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Jonasson, Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Logander, Elisabeth
    Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Nilsson, Lennart
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Swahn, Eva
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Large early variation of residual platelet reactivity in Acute Coronary Syndrome patients treated with clopidogrel: Results from Assessing Platelet Activity in Coronary Heart Disease (APACHE).2015Inngår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, nr 2, s. 335-340Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: There is a large inter-individual variation in response to clopidogrel treatment and previous studies have indicated higher risk of thrombotic events in patients with high residual platelet reactivity (HRPR), but the optimal time-point for testing is not established. The aim of this study was to investigate the optimal time-point for aggregometry testing and the risk of major adverse cardiac events associated with HRPR.

    METHOD AND RESULTS: We included 125 patients with ACS (73 with STEMI, and 71 received abciximab). The prevalence of HRPR varied substantially over time. The rate of HRPR in patients treated and not treated with abciximab were 43% vs 67% (p=0.01) before, 2% vs 23% (p=0.001) 6-8h after, 8% vs 9% (p=0.749) 3days after, and 23% vs 12% (p=0.138) 7-9 days after loading dose of clopidogrel. We found HRPR in 18% of the patients but only four ischemic events during 6months follow-up, with no significant difference between HRPR patients compared to the rest of the population. There were 3 TIMI major bleedings, all of which occurred in the low residual platelet reactivity (LRPR) group.

    CONCLUSION: There is a large variation in platelet reactivity over time, also depending on adjunctive therapy, which has a large impact on optimal time-point for assessment. We found HRPR in almost 1 in 5 patients, but very few MACE, and not significantly higher in HRPR patients. In a contemporary ACS population, with low risk for stent thrombosis, the predictive value of HRPR for ischemic events will probably be low.

  • 2.
    Amatya, B
    et al.
    Karolinska University Hospital.
    El-Nour, H
    Karolinska University Hospital.
    Holst, M
    Astrid Lindgren Childrens Hospital.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Nordlind, K
    Karolinska University Hospital.
    Expression of tachykinins and their receptors in plaque psoriasis with pruritus2011Inngår i: BRITISH JOURNAL OF DERMATOLOGY, ISSN 0007-0963, Vol. 164, nr 5, s. 1023-1029Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pandgt;Background Cutaneous melanoma is rapidly increasing in incidence worldwide and approximately 5% of melanomas are hereditary. Deletions in chromosome 1p36 have been detected in melanoma but no candidate melanoma tumour suppressor gene has yet been found in this area. Recently, strong evidence has been reported that CHD5 is a tumour suppressor gene in this region. Objectives To investigate CHD5 involvement in familial melanoma. Methods Peripheral blood DNA from 47 melanoma families who do not carry mutations in any of the three currently recognized melanoma genes, 398 patients with sporadic melanoma and 398 geographically matched nonmelanoma-bearing controls were studied. Linkage investigation, single nucleotide polymorphism (SNP) genotyping and mutation screening studies were carried out on the CHD5 locus. Results The CHD5 gene was not excluded by linkage analysis in any of the families. On SNP genotyping, the CHD5 rs7513548 SNP was found to be significantly associated with sporadic melanoma (odds ratio 1 center dot 53, 95% confidence interval 1 center dot 13-2 center dot 06). The AG genotype was found in 208 cases and 169 controls (cf. 141 and 175 cases and controls, respectively, for the AA genotype). On CHD5 mutation screening, a total of 50 single-base substitutions were detected. Of these, 39 were intronic and 11 were exonic. While 32 were previously recognized variants, 18 were newly identified. Three, in exons 4, 31 and 32, led to nonsynonymous substitutions. A p.Met1576Ile substitution was identified in a mother and daughter, both with invasive cutaneous melanoma. Conclusions This study appears to be the first report of CHD5 variants in familial cutaneous melanoma. Such CHD5 variants could block or alter the ability of CHD5 to regulate the cell cycle pathway and to effect cellular control. As only one of the 47 families studied has this variant, it appears to be a rare event and further screening of melanoma families is required to confirm whether or not CHD5 is involved in melanoma pathogenesis.

  • 3.
    Arbring, Kerstin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Chaireti, Roza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Janzon, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Jansson, Kjell
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Fysiologiska kliniken US.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    First experience of structured introduction of new oral anticoagulants in a Swedish health care district: dabigatran as an alternative to warfarin in atrial fibrillation2013Konferansepaper (Fagfellevurdert)
  • 4.
    Arbring, Kerstin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Comparison of prothrombin time (INR) results and main characteristics of patients on warfarin treatment in primary health care centers and anticoagulation clinics2013Inngår i: BMC Health Services Research, ISSN 1472-6963, E-ISSN 1472-6963, Vol. 13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Oral anticoagulant therapy is used to prevent thrombosis in patients with atrial fibrillation (AF), venous thrombosis and prosthetic heart valves. The introduction of new therapies emphasizes the need to discern the best practice for the patients remaining on warfarin treatment. This study compares patient characteristics and therapeutic control in two settings managing warfarin treatment: Swedish primary health care centers (PHCC) and specialized anticoagulation clinics (ACC).

    Methods

    Prothrombin time (PT) test results reported as International Normalized Ratio (INR) were collected for five consecutive days from patients on warfarin treatment; 564 PHCC and 927 ACC patients. Therapeutic control was calculated as PT test results in relation to intended therapeutic range (TR). Mann–Whitney Rank Sum Test and Chi2 test were used for statistical comparisons.

    Results

    The PHCC patients were older than the ACC patients, 76 v. 70 years (p<0.01) with a predominance of men in both groups. The reasons for treating differed between the groups. Seventy-two percent of PHCC patients and 66% of ACC patients had a PT-INR within the intended TR (p<0.05). Men generally had better results than women (72% v. 63%, p<0.001) and particularly in the PHCC group v. the ACC group (78% v. 69%, p<0.01).

    PT-INR above intended TR was significantly more common in the ACC setting, (p<0.05), for women overall (p<0.01), for women in the PHCC setting, and for ACC men (p<0.05).

    Conclusions

    In this study both settings achieved good therapeutic control of warfarin treatment with a minor advantage for PHCC over ACC, and better results for men, especially in the PHCC setting. As patient characteristics differ between the PHCC and ACC, it is important to conduct further randomized studies to discern the best practice locally for warfarin management also after the introduction of new drugs.

  • 5.
    Aspenberg, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening2011Inngår i: BONE, ISSN 8756-3282, Vol. 48, nr 2, s. 225-230Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Orthopedic joint prostheses may loosen because of localized bone resorption. Despite initial optimism, there are no reports showing that bisphosphonates can stop the progression of prosthetic loosening once it has begun. This might be due to the strong resorptive stimulus, which continuously recruits new osteoclasts. Therefore, we hypothesized that a treatment targeting osteoclast recruitment would be more efficacious than a treatment reducing osteoclast activity. We used a previously described rat model for instability-induced bone resorption, and compared OPG-Fc with alendronate at a clinically relevant or an extreme dose. A titanium plate was osseointegrated at the rat tibial surface. Instability was simulated by a piston, moving perpendicularly to the bone surface. Piston movement induced bone loss via hydrostatic pressure or fluid flow. Rats were randomized to 5 groups (total n = 56), of which 4 were subjected to instability and one was stable. The unstable groups were injected with either high-dose OPG-Fc (10 mg/kg, twice weekly), a high dose of alendronate (20 mu g /kg/day), an extreme dose of alendronate (200 mu g/kg/day) or saline. Significant protection against resorption could only be shown for OPG-Fc and the extreme alendronate dose. Both alendronate doses reduced serum levels of tartrate-resistant acid phosphatase isoform 5b to a similar extent, demonstrating that the lower dose was able to reduce resorption in the normally remodeling skeleton, although not in the osteolytic lesions caused by instability. Osteoclast numbers in the lesion were increased by the lower bisphosphonate dose and reduced by OPG-Fc. The results suggest the possibility of targeting osteoclast recruitment via the RANKL system in patients with impending prosthetic loosening.

  • 6.
    Bastami, Salumeh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Practical and clinical use of opioids2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Pain is a common symptom of a number of conditions including cancer and one of the most frequent reasons for seeking healthcare. Acute and chronic pain result in considerable discomfort with a detrimental impact on the quality of life. Opioids are the mainstay of pain management for many patients with severe pain. Opioids are, unfortunately, also commonly abused drugs, and are well-represented in forensic toxicology investigations.

    Side effects related to the central nervous system are the major reasons fordiscontinuation of opioid treatment. In this thesis, we tested the hypothesis that local analgesic treatment by opioids, without the usual opioid-related side effects, could be a potential alternative to systemic opioid treatment. We examined the analgesic effect of topically applied morphine in a randomized, double blind, cross over study in patients with painful leg ulcers. Significant reduction of pain was obtained after application of both morphine and placebo gel. Morphine reduced pain more than placebo but the difference was not statistically significant. However, morphine could reduce pain considerably more than placebo in those cases where VAS (Visual analog scale) was higher initially.

    Another issue with opioid therapy is the substantial individual variability in response to opioids including morphine and tramadol. We investigated the significance of UGT2B7, CYP2D6, OPRM1 and ABCB1 polymorphisms for pharmacokinetic and pharmacodynamic properties of morphine and tramadol. We showed that genetic variants in CYP2D6 and UGT2B7 have an important role in the metabolism of tramadol and morphine respectively. While the role of SNPs in ABCB1 remained unclear, genetic variants in OPRM1 gene were correlated with the required dose of morphine. Taken together, these findings suggest that genotypes should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results.

    Opioids, besides their analgesic properties, have other pharmacological effects including effects on immune system. We evaluated potential differences between commonly used opiates with regard to their effect on the immune system. We found an inhibition of cytokine release, in the order of potency as follows: tramadol > ketobemidone >morphine >fentanyl. All opioids with the exception of fentanyl were capable of inhibiting production of mRNAs for TNF-alpha and IL-8. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of opioids and to improve opioid treatment strategies in patients with cancer.

    Here, we have found that individual genotype matters and affects the individual response. Further research is warranted to tailor individualized treatment. Personalized medicine has increased in importance and will hopefully in the near future become standard procedure to improve and predict the outcome of treatment by opioids.

    Delarbeid
    1. Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial: a pilot study
    Åpne denne publikasjonen i ny fane eller vindu >>Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial: a pilot study
    2012 (engelsk)Inngår i: International Wound Journal, ISSN 1742-4801, E-ISSN 1742-481X, Vol. 9, nr 4, s. 419-427Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Chronic painful wounds, a major health problem, have a detrimental impact on the quality of life due to associated pain. Some clinical reports have suggested that local administration of morphine could be beneficial. The aim of this study was to evaluate the analgesic effect of topically applied morphine on chronic painful leg ulcers. Twenty-one patients were randomly assigned to receive either morphine or placebo in a randomised, placebo-controlled, crossover pilot study. Each patient was treated four times in total. Pain was measured by the visual analogue score (VAS) before application of gel, directly after and after 2, 6, 12 and 24 hours. Although an overall, clinically relevant, reduction of pain was observed upon treatment with morphine, the difference was not statistically significant. Morphine reduced pain scores more than placebo on treatment occasions 1 and 2. The difference was statistically significant only 2 hours after dressing on the first treatment occasion. Thus, our study did not demonstrate a consistent and globally significant difference in nociception in patients treated with morphine. However, the relatively small number of patients included in our study and other methodological limitations makes it difficult for us to draw general conclusions regarding efficacy of topically applied morphine as an effective treatment for some painful ulcers. Further studies are warranted to evaluate the value of topically applied morphine in the treatment of patients with chronic painful leg ulcers.

    sted, utgiver, år, opplag, sider
    Blackwell Publishing, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-75512 (URN)10.1111/j.1742-481X.2011.00901.x (DOI)000306406000011 ()22151619 (PubMedID)
    Tilgjengelig fra: 2012-03-05 Laget: 2012-03-05 Sist oppdatert: 2017-12-07
    2. Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use
    Åpne denne publikasjonen i ny fane eller vindu >>Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use
    Vise andre…
    2014 (engelsk)Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, nr 5, s. 423-431Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in, both, effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7, OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsy cases as morphine is also a very commonly abused drug

    Blood samples were collected from 40 patients following abdominal hysterectomy, 24 hours after initiation of analgesia through a PCA pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsy cases found positive for morphine in routine forensic analysis.

    Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. Dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood.

    Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients.

    We conclude that gene polymorphisms contribute significantly to the variation in morphine levels observed in individual patients.

    sted, utgiver, år, opplag, sider
    Wiley, 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-96791 (URN)10.1111/bcpt.12248 (DOI)000344015300008 ()24703092 (PubMedID)
    Tilgjengelig fra: 2013-08-27 Laget: 2013-08-27 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    3. Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics
    Åpne denne publikasjonen i ny fane eller vindu >>Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Purpose: There is a significant interindividual variation in the response to tramadol (TRA), which can partly be explained by genetic variation. The main purpose of this study was to determine if there is a correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA (MR) and time after drug administration. We also studied the association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA.

    Methods: Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report drug related symptoms (DRS) during the experimental day.

    Results: We found a positive correlation between MR and the time after drug intake for both intermediate metabolizers (IMs) and extensive metabolizers (EMs). For the only poor metabolizer (PM) with detectable ODT levels the MR was almost constant. The AUC MR and Cmax MR were associated with CYP2D6 genotype, showing the highest mean values for EMs. Multiple regression analysis showed that 56% of the  variation in AUC MR could be explained by CYP2D6 alone and 78% by investigated SNPs altogether. There was great interindividual variation in DRS, but no associations could be found between DRS and investigated polymorphisms.

    Conclusions: MR can be used for estimation of the time of drug intake when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study. We propose that pharmacogenetics should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results, more specifically CYP2D6 genotypes when interpreting the pharmacokinetics of TRA.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-96792 (URN)
    Tilgjengelig fra: 2013-08-27 Laget: 2013-08-27 Sist oppdatert: 2013-08-27bibliografisk kontrollert
    4. Inhibitory effect of opiates on LPS mediated release of TNF and IL-8
    Åpne denne publikasjonen i ny fane eller vindu >>Inhibitory effect of opiates on LPS mediated release of TNF and IL-8
    Vise andre…
    2013 (engelsk)Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, nr 5, s. 1022-1033Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.

    sted, utgiver, år, opplag, sider
    Informa Healthcare, 2013
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-89960 (URN)10.3109/0284186X.2012.737932 (DOI)23145506 (PubMedID)
    Tilgjengelig fra: 2013-03-12 Laget: 2013-03-12 Sist oppdatert: 2017-12-06
  • 7.
    Bastami, Salumeh
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Frödin, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial: a pilot study2012Inngår i: International Wound Journal, ISSN 1742-4801, E-ISSN 1742-481X, Vol. 9, nr 4, s. 419-427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chronic painful wounds, a major health problem, have a detrimental impact on the quality of life due to associated pain. Some clinical reports have suggested that local administration of morphine could be beneficial. The aim of this study was to evaluate the analgesic effect of topically applied morphine on chronic painful leg ulcers. Twenty-one patients were randomly assigned to receive either morphine or placebo in a randomised, placebo-controlled, crossover pilot study. Each patient was treated four times in total. Pain was measured by the visual analogue score (VAS) before application of gel, directly after and after 2, 6, 12 and 24 hours. Although an overall, clinically relevant, reduction of pain was observed upon treatment with morphine, the difference was not statistically significant. Morphine reduced pain scores more than placebo on treatment occasions 1 and 2. The difference was statistically significant only 2 hours after dressing on the first treatment occasion. Thus, our study did not demonstrate a consistent and globally significant difference in nociception in patients treated with morphine. However, the relatively small number of patients included in our study and other methodological limitations makes it difficult for us to draw general conclusions regarding efficacy of topically applied morphine as an effective treatment for some painful ulcers. Further studies are warranted to evaluate the value of topically applied morphine in the treatment of patients with chronic painful leg ulcers.

  • 8.
    Bastami, Salumeh
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Gupta, A.
    Department of Anesthesia and Intensive Care, Örebro University, Örebro, Sweden.
    Zackrisson, Anna Lena
    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.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use2014Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, nr 5, s. 423-431Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in, both, effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7, OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsy cases as morphine is also a very commonly abused drug

    Blood samples were collected from 40 patients following abdominal hysterectomy, 24 hours after initiation of analgesia through a PCA pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsy cases found positive for morphine in routine forensic analysis.

    Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. Dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood.

    Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients.

    We conclude that gene polymorphisms contribute significantly to the variation in morphine levels observed in individual patients.

  • 9.
    Bastami, Salumeh
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Haage, Pernilla
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Kugelberg, Fredrik C.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Zackrisson, Anna Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamicsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Purpose: There is a significant interindividual variation in the response to tramadol (TRA), which can partly be explained by genetic variation. The main purpose of this study was to determine if there is a correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA (MR) and time after drug administration. We also studied the association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA.

    Methods: Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report drug related symptoms (DRS) during the experimental day.

    Results: We found a positive correlation between MR and the time after drug intake for both intermediate metabolizers (IMs) and extensive metabolizers (EMs). For the only poor metabolizer (PM) with detectable ODT levels the MR was almost constant. The AUC MR and Cmax MR were associated with CYP2D6 genotype, showing the highest mean values for EMs. Multiple regression analysis showed that 56% of the  variation in AUC MR could be explained by CYP2D6 alone and 78% by investigated SNPs altogether. There was great interindividual variation in DRS, but no associations could be found between DRS and investigated polymorphisms.

    Conclusions: MR can be used for estimation of the time of drug intake when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study. We propose that pharmacogenetics should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results, more specifically CYP2D6 genotypes when interpreting the pharmacokinetics of TRA.

  • 10.
    Bastami, Salumeh
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Haage, Pernilla
    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.
    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.
    Kugelberg, Fredrik
    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.
    Zackrisson, Anna-Lena
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose2014Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 238, s. 125-132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The major purpose of this study was to elucidate if genotyping can facilitate interpretations of tramadol (TRA) in forensic case work, with special regard to the estimation of the time of drug intake and drug related symptoms (DRS). The association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA was studied. Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report DRS during the experimental day. We found a positive correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA and the time after drug intake for both CYP2D6 intermediate metabolizers and extensive metabolizers. For the only poor metabolizer with detectable ODT levels the metabolic ratio was almost constant. Significant associations were found between the area under the concentration-time curve (AUC) and three of the investigated ABCB1 single nucleotide polymorphisms for TRA, but not for ODT and only in the 50 mg dosage group. There was great interindividual variation in DRS, some subjects exhibited no symptoms at all whereas one subject both fainted and vomited after a single therapeutic dose. However, no associations could be found between DRS and investigated polymorphisms. We conclude that the metabolic ratio of ODT/TRA may be used for estimation of the time of drug intake, but only when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study.

  • 11.
    Bastami, Salumeh
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Norling, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Trinks, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Walz, Thomas M
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Inhibitory effect of opiates on LPS mediated release of TNF and IL-82013Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, nr 5, s. 1022-1033Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.

  • 12.
    Bellanti, Francesco
    et al.
    Division of Pharmacology, Leiden/Amsterdam Centre Drug Research, Leiden, The Netherlands.
    Kågedal, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Della Pasqua, Oscar
    Division of Pharmacology, Leiden/Amsterdam Centre Drug Research, Leiden, The Netherlands.
    Do pharmacokinetic polymorphisms explain treatment failure in high-risk patients with neuroblastoma?2011Inngår i: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, ISSN 0031-6970, Vol. 67, s. S87-S107Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Purpose Neuroblastoma is the most common extracranial solid tumour in childhood. It accounts for 15% of all paediatric oncology deaths. In the last few decades, improvement in treatment outcome for high-risk patients has not occurred, with an overall survival rate andlt;30-40%. Many reasons may account for such a low survival rate. The aim of this review is to evaluate whether pharmacogenetic factors can explain treatment failure in neuroblastoma. Methods A literature search based on PubMeds database Medical Subject Headings (MeSH) was performed to retrieve all pertinent publications on current treatment options and new classes of drugs under investigation. One hundred and fifty-eight articles wer reviewed, and relevant data were extracted and summarised. Results and conclusions Few of the large number of polymorphisms identified thus far showed an effect on pharmacokinetics that could be considered clinically relevant. Despite their clinical relevance, none of the single nucleotide polymorphisms (SNPs) investigated can explain treatment failure. These findings seem to reflect the clinical context in which anti-tumour drugs are used, i.e. in combination with multi-modal therapy. In addition, many pharmacogenetic studies did not assess (differences in) drug exposure, which could contribute to explaining pharmacogenctic associations. Furthermore, it remains unclear whether the significant activity of new drugs on different neuroblastoma cell lines translates into clinical efficacy, irrespective of resistance or myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification. Elucidation of the clinical role of pharmacogenetic factors in the treatment of neuroblastoma demands an integrated pharmacokinetic pharmacodynamic approach to the analysis of treatment response data.

  • 13.
    Bergh, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Evaldsson, Chamilly
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Pedersen, Lone Bredo
    Rigshospitalet Copenhagen, Denmark.
    Geisler, Christian
    Rigshospitalet Copenhagen, Denmark.
    Stamatopoulos, Kostas
    G. Papanicolaou Hospital, Greece.
    Rosenquist, Richard
    Rudbeck Laboratory, Uppsala University, Sweden .
    Rosén, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia2014Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, nr 11, s. 1722-1730Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chronic lymphocytic leukemia B-cells express auto/xeno-antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen, since it is more faithful to B-cell physiology than anti-IgM, for analysis of downstream B-cell receptor-signal transduction events. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen-binding induced prompt receptor-clustering, followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca2+ mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48 hours culture in the absence of antigen in half of the cases. Toll-like receptor 9-ligand was found to breach the B-cell receptor-signaling incompetence in 5 of 12 cases pointing to intra-subset heterogeneity. Altogether, this study supports B-cell receptor-unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia indicating that these cells proliferate by other mechanisms that may override B-cell receptor-silencing brought about in a context of self-tolerance/anergy. These novel findings have implications for the understanding of chronic lymphocytic leukemia pathobiology and therapy.

  • 14.
    Bjorses, Katarina
    et al.
    Lund University.
    Faxälv, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Montan, Carl
    Lund University.
    Wildt-Persson, Katarina
    Magle Life Science.
    Fyhr, Peter
    Magle Life Science.
    Holst, Jan
    Lund University.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    In vitro and in vivo evaluation of chemically modified degradable starch microspheres for topical haemostasis2011Inngår i: ACTA BIOMATERIALIA, ISSN 1742-7061, Vol. 7, nr 6, s. 2558-2565Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Degradable starch microspheres (DSMs) are starch chains cross-linked with epichlorhydrin, forming glycerol-ether links. DSMs have been used for many years for temporary vascular occlusion and drug delivery in treatment of malignancies. They are also approved and used for topical haemostasis by absorbing excess fluid from the blood and concentrating endogenous coagulation factors, thereby facilitating haemostasis. This mechanism of action is not sufficient for larger bleedings in current chemical formulations of DSMs, and modification of DSMs to trigger activation of platelets or coagulation would be required for use in such applications. Chemical modifications of DSMs with N-octenyl succinic anhydride, chloroacetic acid, acetic anhydride, diethylaminoethyl chloride and ellagic acid were performed and evaluated in vitro with thrombin generation and platelet adhesion tests, and in vivo using an experimental renal bleeding model in rat. DSMs modified to activate platelets in vitro were superior in haemostatic capacity in vivo. Further studies with non-toxic substances are warranted to confirm these results and develop the DSM as a more effective topical haemostatic agent.

  • 15.
    Boij, R
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Berg, Göran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Nilsson-Ekdahl, K
    Uppsala University.
    Svensson, J
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Sandholm, K
    Linneus University.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Matthiesen, Leif
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Palonek, E
    Karolinska University.
    Jarle, M
    Karolinska University.
    Biomarkers of coagulation, inflammation and angiogenesis are independently associated with preeclampsia in JOURNAL OF REPRODUCTIVE IMMUNOLOGY, vol 94, issue 1, pp 109-1092012Inngår i: JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Elsevier , 2012, Vol. 94, nr 1, s. 109-109Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 16.
    Boij, Roland
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Judit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson-Ekdahl, Kristina
    Uppsala University, Sweden Linneaus University, Sweden .
    Sandholm, Kerstin
    Linneaus University, Sweden .
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Palonek, Elzbieta
    Karolinska University Hospital, Sweden Doping Control Lab, Sweden .
    Garle, Mats
    Karolinska University Hospital, Sweden Doping Control Lab, Sweden .
    Berg, Göran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Matthiesen, Leif
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia2012Inngår i: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, ISSN 1046-7408, Vol. 68, nr 3, s. 258-270Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.

  • 17.
    Boknäs, Niklas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Faxälv, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Lindahl, Tomas L
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Contact activation: important to consider when measuring the contribution of tissue factor-bearing microparticles to thrombin generation using phospholipid-containing reagents2014Inngår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, nr 4, s. 515-518Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background A commercial MP reagent containing phospholipids is used for thrombin generation (TG) measurements to estimate the procoagulant activity of microparticles (MPs). Previous reports have shown that contact activation affects TG when TF levels are low, and that addition of phospholipids might augment this effect. Objectives To quantify the impact of contact activation on TG in the presence of phospholipids and low/no TF, as is the case using a commercially available MP-reagent. Methods Thrombin generation was analyzed using MP- or platelet-rich plasma (PRP)-reagent in the presence and absence of corn trypsin inhibitor and anti-TF antibodies, respectively. To quantify the impact of different experimental parameters on contact activation, microparticle-depleted plasma was analyzed in the presence of different concentrations of phospholipids, TF and/or contact activating agents (kaolin). Results Even with low contact activating blood collection tubes, substantial thrombin generation was observed with the MP-reagent, but this was completely inhibited by addition of corn trypsin inhibitor. Control experiments illustrate that the phospholipids in the reagent play a major role in enhancing TG initiated by FXIIa. Even with the PRP-reagent, which is recommended for determining the content of phospholipids from MPs, TG was partly dependent on contact activation. Conclusions Contact activation plays a major role in TG when using reagents/samples containing phospholipids but little or no tissue factor. This needs to be considered and accounted for in future clinical studies using TG to assess the procoagulant activity of MPs.

  • 18.
    Boknäs, Niklas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Faxälv, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Sanchez Centellas, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Wallstedt, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Grenegård, Magnus
    University of Örebro, Sweden.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Thrombin-induced platelet activation via PAR4: pivotal role for exosite II2014Inngår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, nr 3, s. 558-565Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Although the underlying mechanisms responsible for ensuring efficient PAR1 activation by thrombin have been extensively studied, the potential involvement of recognitions sites outside the active site of the protease in thrombin-induced PAR4 activation is largely unknown. In this study, we developed a new assay to assess the importance of exosite I and II for PAR4 activation with alpha- and gamma-thrombin. Surprisingly, we found that exosite II is critical for activation of PAR4. We also show that this dependency on exosite II likely represents a new mechanism, as it is unaffected by blockage of the previously known interaction between thrombin and glycoprotein Ib alpha.

  • 19.
    Boknäs, Niklas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Faxälv, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Ström, Jakob O
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    Sahlgrenska Academy, University of Gothenburg, Sweden.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas L
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Response: platelets do not generate activated factor XII--how inappropriate experimental models have led to misleading conclusions2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 10, s. 1692-1694Artikkel i tidsskrift (Annet vitenskapelig)
  • 20.
    Brynhildsen, Jan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Sydsjö, Gunilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Blomberg, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Claesson, Ing-Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Nyström, Fredrik H.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrinmedicinska enheten.
    Sydsjö, Adam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Josefsson, Ann
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Leptin and adiponectin in cord blood from children of normal weight, overweight and obese mothers2013Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 102, nr 6, s. 620-624Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim To study cord blood concentrations of adiponectin and leptin in children born by normal weight, overweight and obese mothers and to study these parameters in relation to a weight gain intervention programme for obese mothers. Methods Ten millilitre cord blood was collected and analysed for leptin and adiponectin concentrations in children with gestational age andgt;37weeks born by 60 normal weight, 45 overweight and 145 obese mothers. 82 obese mothers took part in a weight gain intervention programme. Results Concentrations of leptin and adiponectin were higher in cord blood from children of overweight and obese mothers compared with children of normal weight mothers (leptin: Md 13.2, 30, 3 and 90.2ng/mL respectively, pandlt;0.001; adiponectin 35.9, 205.4, 213.8ng/L pandlt;0.001). No differences were found between overweight and obese mothers. The weight gain intervention programme for obese pregnant women had significant effects on the weight gain during pregnancy but had no effects on cord blood serum concentrations of leptin and adiponectin. Conclusion Cord blood leptin and adiponectin concentrations were higher in children born by overweight or obese women compared with children of normal weight mothers. A weight gain intervention programme for obese pregnant women did not affect these results. Intrauterine exposition to high concentrations of leptin and adiponectin may play a role in weight development later in life.

  • 21.
    Carlson, Joyce
    et al.
    EpiHealth: Epidemiology for Health, Lunds universitet.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Lindstedt, Göran
    Sahlgrenska akademin, Göteborgs universitet.
    Digestionsorganens sjukdomar2012Inngår i: Laurells Klinisk kemi i praktisk medicin / [ed] Peter Nilsson-Ehle, Maria Berggren Söderlund, Elvar Theodorsson, Lund, 2012, 9, s. 441-496Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [sv]

    Klinisk kemi i praktisk medicin används som kurslitteratur för läkare, biomedicinska analytiker och biomedicinare sedan 40 år tillbaka. Den finns på avdelningar, mottagningar och vårdcentraler - överallt där man behöver ta prover för kliniskt kemiska analyser och tolka deras resultat. Nu föreligger den i sin nionde upplaga efter omfattande revision och med nyskrivna kapitel. I denna upplaga har innehållet organiserats med tydlig anknytning till kliniska problemområden. Alla kapitel har grundligt reviderats. Avsnitten om tolkning av analysresultat, allergi och autoimmunitet, hjärtinfarkt och hjärtskademarkörer, digestionsorganens sjukdomar, graviditet, infertilitet och prenataldiagnostik samt läkemedel, förgiftningar och missbruk är helt nyskrivna. Boken kan användas både för att slå upp fakta om specifika analyser och för att förstå de sjukdomsmekanismer som är av betydelse för tolkningen av laboratorieresultat. Modern medicinsk praxis är patientcentrerad och har sitt fundament i ett nära samspel mellan klinik, laboratorier och patienter. Kunskapsfragment inom klinisk kemi är lättillgängliga för alla och envar på nätet, men ger sällan den helhetsbild som behövs för grundlig förståelse och därmed optimal användning av laboratorieanalyser. Denna bok ger sådan helhetsbild.

  • 22.
    Chaireti, Roza
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Gustafsson, K M.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Bystrom, B
    Karolinska Institute, Sweden .
    Bremme, K
    Karolinska Institute, Sweden .
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Endogenous thrombin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle2013Inngår i: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 28, nr 7, s. 1846-1852Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Do thrombin generation and haemostatic parameters differ during the two phases of the menstrual cycle? less thanbrgreater than less thanbrgreater thanTotal thrombin concentration is higher during the luteal phase compared with the follicular phase of the menstrual cycle. less thanbrgreater than less thanbrgreater thanThe coagulation cascade is affected by many variables, such as fluctuations in the levels of sex hormones. The studies on the variations in haemostatic parameters during the menstrual cycle have produced diverse results. less thanbrgreater than less thanbrgreater thanThrombin generation and selected haemostatic parameters (fibrinogen, factor II, factor VII, factor VIII, factor X, von Willebrand factor, antithrombin and D-dimer) were measured during the two phases of a normal menstrual cycle in 102 healthy women not taking any form of hormone medication. less thanbrgreater than less thanbrgreater thanThe study cohort consisted of 102 healthy women with regular menstrual cycles. Thrombin generation was measured by the calibrated automated thrombogram method. Progesterone and sex hormone-binding globulin were measured by chemiluminescence enzyme immunoassays. Estradiol was measured by a sensitive radioimmunoassay. Fibrinogen was measured by a clotting method, antithrombin was measured by a chromogenic method and factor II, factor VII, factor VIII, factor X, von Willebrand factor and D-dimer were measured by photometric methods. less thanbrgreater than less thanbrgreater thanIt was shown that the total amount of generated thrombin (Endogenous Thrombin Potential) was significantly higher during the luteal compared with the follicular phase (P 0.027). Factor X was significantly higher during the follicular phase (P 0.028). Progesterone exhibited significant associations (measured by the least squares regression analysis) with fibrinogen and factor X during the follicular phase (P 0.043 and P 0.033, respectively) and with factors II and VII during the luteal phase (P 0.034 and P 0.024, respectively). The validity of the results from the regression analysis was further confirmed by performing correlation analyses (Pearson correlation matrix) for haemostatic markers for the luteal and follicular phases (accepted correlation level 0.8). less thanbrgreater than less thanbrgreater thanThe wide confidence interval for the differences in endogenous thrombin potential during the two phases could imply that the size of the cohort may not be sufficient to fully evaluate the biological variations. Additionally, the haemostatic markers were not shown to have significant associations with thrombin generation, suggesting that the increased thrombin concentration during the luteal phase would be mediated by another mechanism, as yet unidentified. less thanbrgreater than less thanbrgreater thanThe associations between progesterone and the haemostatic markers, as shown for both phases of the menstrual cycle, suggest a previously unknown or undefined yet potentially significant role for progesterone in the coagulation system. However, it has been shown that the use of progestogen-only preparations does not affect the coagulation system, which is partly the reason why they are considered safe for women with thrombophilia or previous thrombotic event. Further studies are required in order to demonstrate whether our results can be extrapolated for synthetic progestins, which might have significant implication on the indications for their use. less thanbrgreater than less thanbrgreater thanThis study was supported by the Karolinska Institutet, Linkping University and the County Council of stergtland. The authors report no conflicts of interest.

  • 23.
    Chaireti, Roza
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Jennersjö, Cecilia
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Is thrombin generation at the time of an acute thromboembolic episode a predictor of recurrence? The LInkoping Study on Thrombosis (LIST) - A 7-year follow-up2013Inngår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 131, nr 2, s. 135-139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Venous thromboembolism(VTE) is considered a chronic disease, since a high percentage of patients experience recurrences. Oral anticoagulants are effective in preventing recurrences at a price of potential bleeding complications, which underlines the importance of finding reliable markers for estimating the individual recurrence risk. In this report we evaluate thrombin generation markers at the time of an acute VTE as predictive markers for recurrence risk. Gender, presence of factor V Leiden and acquired provocative factors were taken into consideration. Additionally, we study the correlation between thrombin generation at the time of an acute VTE and thrombin generation measured four to eight weeks after discontinuation of anticoagulants. less thanbrgreater than less thanbrgreater thanMaterials and Methods: Themain cohort consisted of 115 patients with a confirmed thromboembolic event at inclusion. The follow-up period was seven years. less thanbrgreater than less thanbrgreater thanResults: Patients with an initial unprovoked VTE and at least one recurrence had significantly prolonged thrombin generation, whereas those without recurrences had higher maximum and total thrombin concentration. In contrast, when thrombin generation was measured one to two months after discontinuation of anticoagulant treatment, it was shown that the patients who experienced recurrences had higher maximum thrombin concentration. less thanbrgreater than less thanbrgreater thanConclusions: Our study shows that thrombin generation profiles at the time of a VTE correlate to the clinical course after the acute episode. The great over-lap in thrombin generation between patients with and without recurrences though, makes the use of thrombin generation profiles for advice on length of oral anticoagulation for an individual patient doubtful at the present stage of knowledge.

  • 24.
    Chaireti, Roza
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken. Karolinska Univ Hosp, Coagulat Unit, Div Haematol, Dept Med, Stockholm, Sweden.
    Rajani, Rupesh
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Bergquist, Annika
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Melin, Tor
    Division of Gastroenterology & Hepatology, University Hospital, Lund, Sweden.
    Friis-Liby, Inga-Lill
    Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Kapraali, Marjo
    Karolinska Institutet, Department of Clinical Sciences Danderyd Hospital, Division of Medicine, Stockholm, Sweden.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Lindahl, Tomas L.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Almer, Sven
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Karolinska Inst, Dept Med, Solna, Sweden.
    Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event2014Inngår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, nr 2, s. 455-461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In recent years there have been increasing evidence associating liver disease with hypercoagulability, rather than bleeding.

    Aims: To evaluate the haemostatic potential in patients with liver disease.

    Methods: We measured thrombin generation in the presence and absence of thrombomodulin in patients with portal vein thrombosis (PVT, n=47), Budd-Chiari syndrome (BCS, n=15) and cirrhosis (n=24) and compared the results to those obtained from healthy controls (n=21). Fifteen patients with PVT and 10 patients with BCS were treated with warfarin and were compared with an equal number of patients with atrial fibrillation matched for prothrombin time-international normalized ratio. We assessed resistance to thrombomodulin by using ratios [marker measured in the presence]/[marker measured in the absence of thrombomodulin].

    Results: There were no differences between patients with BCS, patients on warfarin treatment and controls. Cirrhotic patients generated more thrombin in the presence of thrombomodulin and exhibited thrombomodulin resistance compared with controls [p=0.006 for endogenous thrombin potential (ETP) and p<0.001 for peak thrombin. P<0.001 for both ratios ETP and peak] and patients with non-cirrhotic PVT (p=0.001, p=0.006, p<0.001, p<0.001 for ETP, peak, ratio ETP, ratio peak). The patients with cirrhotic PVT exhibited higher ETP (p=0.044) and peak (p=0.02) in the presence of thrombomodulin than controls, as well as thrombomodulin resistance (ETP ratio: p=0.001, peak ratio: p=0.001).

    Conclusions: Hypercoagulability and thrombomodulin resistance in patients with cirrhosis were independent of the presence of splanchnic vein thrombosis. The hypercoagulability in patients with cirrhotic PVT could have implications for considering longer treatment with anticoagulants in this group.

  • 25.
    Dizdar (Dizdar Segrell), Nil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Zsigmond, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurokirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Neurokirurgiska kliniken US.
    Kullman, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Nezirevic, Dzeneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Letter: Untitled2013Inngår i: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 212, nr 2, s. 363-363Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    n/a

  • 26.
    D'Orazio, Paul
    et al.
    Instrumentation Lab, Lexington.
    Burnett, Robert W.
    Hartford Hospital.
    Fogh-Andersen, Niels
    Herlev Hospital.
    Jacobs, Ellis
    Wadsworth Centre.
    Kuwa, Katsuhiko
    University of Tsukuba.
    Kuelpmann, Wolf R.
    Hannover Medical School.
    Larsson, Lasse
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Lewenstam, Andrzej
    Abo Akad University.
    Maas, Anton H. J.
    Eurotrol bv, Ede, Netherlands.
    Mager, Gerhard
    Fresenius, Bad Homburg, Germany.
    Naskalski, Jerzy W.
    Jagiellonian University.
    Okorodudu, Anthony O.
    University of Texas Medical Branch.
    On a recommendation adopted by the IFCC for the report of blood glucose results2008Inngår i: Acta Bioquimica Clinica Latinoamericana, ISSN 0325-2957, E-ISSN 1851-6114, Vol. 42, nr 3, s. 385-389Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    n/a

  • 27.
    Elvers, Margitta
    et al.
    University of Tubingen, Germany .
    Grenegård, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Khoshjabinzadeh, Hanieh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Muenzer, Patrick
    University of Tubingen, Germany .
    Borst, Oliver
    University of Tubingen, Germany University of Tubingen, Germany .
    Tian, Huasong
    Columbia University, NY 10032 USA .
    Di Paolo, Gilbert
    Columbia University, NY 10032 USA .
    Lang, Florian
    University of Tubingen, Germany .
    Gawaz, Meinrad
    University of Tubingen, Germany .
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Fälker, Knut
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    A novel role for phospholipase D as an endogenous negative regulator of platelet sensitivity2012Inngår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, nr 9, s. 1743-1752Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Platelet aggregation, secretion and thrombus formation play a critical role in primary hemostasis to prevent excessive blood loss. On the other hand, uncontrolled platelet activation leads to pathological thrombus formation resulting in myocardial infarction or stroke. Stimulation of heterotrimeric G-proteins by soluble agonists or immunoreceptor tyrosine based activation motif-coupled receptors that interact with immobilized ligands such as the collagen receptor glycoprotein (GP) VI lead to the activation of phospholipases that cleave membrane phospholipids to generate soluble second messengers. Platelets contain the phospholipases (PL) D1 and D2 which catalyze the hydrolysis of phosphatidylcholine to generate the second messenger phosphatidic acid (PA). The production of PA is abrogated by primary alcohols that have been widely used for the analysis of PLD-mediated processes. However, it is not clear if primary alcohols effectively reduce PA generation or if they induce PLD-independent cellular effects. In the present study we made use of the specific PLD inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) and show for the first time, that FIPI enhances platelet dense granule secretion and aggregation of human platelets. Further. FIPI has no effect on cytosolic Ca2+ activity but needs proper Rho kinase signaling to mediate FIPI-induced effects on platelet activation. Upon FIPI treatment the phosphorylation of the PKC substrate pleckstrin was prominently enhanced suggesting that FIPI affects PKC-mediated secretion and aggregation in platelets. Similar effects of FIPI were observed in platelets from mouse wild-type and Pld1(-/-) mice pointing to a new role for PLD2 as a negative regulator of platelet sensitivity.

  • 28.
    Erlinge, David
    et al.
    Lund University, Sweden .
    Gurbel, Paul A.
    Sinai Centre Thrombosis Research, MD USA .
    James, Stefan
    Uppsala University, Sweden .
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Svensson, Peter
    Lund University, Sweden .
    Ten Berg, Jurrien M.
    St Antonius Hospital, Netherlands .
    Foley, David P.
    Beaumont Hospital, Ireland .
    Wagner, Henrik
    Lund University, Sweden .
    Brown, Patricia B.
    Eli Lilly and Co, IN USA .
    Luo, Junxiang
    Eli Lilly and Co, IN USA .
    Zhou, Chunmei
    Eli Lilly and Co, IN USA .
    Moser, Brian A.
    Eli Lilly and Co, IN USA .
    Jakubowski, Joseph A.
    Eli Lilly and Co, IN USA .
    Small, David S.
    Eli Lilly and Co, IN USA .
    Winters, Kenneth J.
    Eli Lilly and Co, IN USA .
    Angiolillo, Dominick J.
    University of Florida, FL USA .
    Prasugrel 5 mg in the Very Elderly Attenuates Platelet Inhibition But Maintains Noninferiority to Prasugrel 10 mg in Nonelderly Patients2013Inngår i: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 62, nr 7, s. 577-583Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (andgt;= 75 years of age). less thanbrgreater than less thanbrgreater thanBackground In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients. less thanbrgreater than less thanbrgreater thanMethods We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 +/- 3 years of age) or (n 82) nonelderly (NE) (andgt;= 45 to andlt;65 years of age; mean: 56 +/- 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1-sided 97.5% confidence interval for the difference andlt;15%. less thanbrgreater than less thanbrgreater thanResults Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 +/- 14%) than clopidogrel (63 +/- 14%; p andlt; 0.001) in VE but higher than prasugrel 10 mg in NE (46 +/- 12%; p andlt; 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg. less thanbrgreater than less thanbrgreater thanConclusions In aspirin-treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912)

  • 29.
    Evaldsson, Chamilly
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Rydén, Ingvar
    Division of Clinical Chemistry, Kalmar County Hospital, Kalmar, Sweden.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Isomaltitol exacerbates neutrophilia but reduces eosinophilia: New insights into the Sephadex model of lung inflammation2011Inngår i: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 154, nr 4, s. 286-294Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously examined isomaltitol in an in vitro static adhesion assay between isolated granulocytes and cultured human umbilical cord vein cells and were interested in investigating whether the potentially anti-inflammatory effects observed there could be reproduced in vivo. The Sephadex-induced lung inflammation model was considered a suitable model due to the significant changes in global inflammatory endpoints, like oedema and leukocyte migration, usually seen upon provocation with Sephadex.

    Male Sprague-Dawley rats were instilled intratracheally with Sephadex (5 mg/ml), vehicle (0.9% NaCl), isomaltitol (50 mg/ml) or a combination of isomaltitol and Sephadex. After 24 h, the lungs were weighed to measure oedema and preserved for histology. Bronchoalveolar lavage fluid was used for analysis of tumour necrosis factor, cysteinyl leukotrienes, and differential and total leukocyte counts. In addition, blood differential counts and thymus weights were analysed.

    Contrary to what we expected from in vitro experiments, differential counts showed that isomaltitol increased the neutrophil component while decreasing the eosinophilia. Isomaltitol thus asserted a modulatory role on the usually eosinophil-dominated Sephadex-induced cell profile. Isomaltitol alone also increased several inflammatory parameters, including oedema and cysteinyl leukotrienes, and generally aggravated total inflammation in combination with Sephadex. Although the mechanisms were not investigated in this study, the effects could relate to a combination of isomaltitol's osmotic and structure-specific properties.

    Our results indicate that isomaltitol can modulate the inflammatory response induced by Sephadex instillation in addition to have pro-inflammatory effects on it its own, and may therefore provide new insights into the mechanisms of this widely used animal model. Sugar alcohols similar to isomaltitol have already been used to aid mucus clearance in cystic fibrosis patients, and it is possible that isomaltitol could also be used for this purpose.

  • 30.
    Faxälv, Lars
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Boknäs, Niklas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    PAR1, PAR4 and GPIB form functional interdependent units in a receptor complex mediating platelet activation by thrombin in JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol 9, issue SI, pp 11-112011Inngår i: JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Wiley-Blackwell , 2011, Vol. 9, nr SI, s. 11-11Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 31.
    Faxälv, Lars
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Boknäs, Niklas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Ström, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    University of Gothenburg, Gothenburg, Sweden .
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII2013Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, nr 23, s. 3818-3824Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Muller et al has been cited greater than100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of less than10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

  • 32.
    Faxälv, Lars
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Bolin, Maria
    Linköpings universitet, Institutionen för teknik och naturvetenskap. Linköpings universitet, Tekniska högskolan.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Berggren, Magnus
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Electronic control of platelet adhesion using conducting polymer microarrays2014Inngår i: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 14, nr 16, s. 3043-3049Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We hereby report a method to fabricate addressable micropatterns of e-surfaces based on the conducting polymer poly(3,4-ethylenedioxythiophene) doped with the anion tosylate (PEDOT:Tos) to gain dynamic control over the spatial distribution of platelets in vitro. With thin film processing and microfabrication techniques, patterns down to 10 mu m were produced to enable active regulation of platelet adhesion at high spatial resolution. Upon electronic addressing, both reduced and oxidized surfaces were created within the same device. This surface modulation dictates the conformation and/or orientation, rather than the concentration, of surface proteins, thus indirectly regulating the adhesion of platelets. The reduced electrode supported platelet adhesion, whereas the oxidized counterpart inhibited adhesion. PEDOT:Tos electrode fabrication is compatible with most of the classical patterning techniques used in printing as well as in the electronics industry. The first types of tools promise ultra-low-cost production of low-resolution (greater than30 mu m) electrode patterns that may combine with traditional substrates and dishes used in a classical analysis setup. Platelets play a pronounced role in cardiovascular diseases and have become an important drug target in order to prevent thrombosis. This clinical path has in turn generated a need for platelet function tests to monitor and assess platelet drug efficacy. The spatial control of platelet adherence presented here could prove valuable for blood cell separation or biosensor microarrays, e.g. in diagnostic applications where platelet function is evaluated.

  • 33.
    Faxälv, Lars
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Hume, Jasmin
    Chalmers.
    Kasemo, Bengt
    Chalmers.
    Svedhem, Sofia
    Chalmers.
    Imaging of blood plasma coagulation at supported lipid membranes2011Inngår i: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 364, nr 2, s. 582-587Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The blood coagulation system relies on lipid membrane constituents to act as regulators of the coagulation process upon vascular trauma, and in particular the 2D configuration of the lipid membranes is known to efficiently catalyze enzymatic activity of blood coagulation factors. This work demonstrates a new application of a recently developed methodology to study blood coagulation at lipid membrane interfaces with the use of imaging technology. Lipid membranes with varied net charges were formed on silica supports by systematically using different combinations of lipids where neutral phosphocholine (PC) lipids were mixed with phospholipids having either positively charged ethylphosphocholine (EPC), or negatively charged phosphatidylserine (PS) headgroups. Coagulation imaging demonstrated that negatively charged SiO(2) and membrane surfaces exposing PS (obtained from liposomes containing 30% of PS) had coagulation times which were significantly shorter than those for plain PC membranes and EPC exposing membrane surfaces (obtained from liposomes containing 30% of EPC). Coagulation times decreased non-linearly with increasing negative surface charge for lipid membranes. A threshold value for shorter coagulation times was observed below a PS content of similar to 6%. We conclude that the lipid membranes on solid support studied with the imaging setup as presented in this study offers a flexible and non-expensive solution for coagulation studies at biological membranes. It will be interesting to extend the present study towards examining coagulation on more complex lipid-based model systems. (C) 2011 Elsevier Inc. All rights reserved.

  • 34.
    Ferrandis, Maria-José
    et al.
    Department of Clinical Chemistry, Blekinge County Hospital, Sweden.
    Ryden, Ingvar
    Department of Clinical Chemistry, Blekinge County Hospital, Sweden.
    Lindahl, Tomas L.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Larsson, Anders
    Department of Medical Sciences, Section of Clinical Chemistry, Uppsala University, Uppsala, Sweden.
    Ruling out cardiac failure: Cost-benefit analysis of a sequential testing strategy with NT-proBNP before echocardiography2013Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, nr 2, s. 75-79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives. To estimate the possible economic benefit of a sequential testing strategy with NT-proBNP to reduce the number of echocardiographies.

    Methods. Retrospective study in a third-party payer perspective. The costs were calculated from three Swedish counties: Blekinge, Östergötland, and Uppland. Two cut-off levels of NT-proBNP were used: 400 and 300 pg/mL. The cost-effectiveness of the testing strategy was estimated through the short-term cost avoidance and reduction in demand for echocardiographies.

    Results. The estimated costs for NT-proBNP tests and echocardiographies per county were reduced by 33%–36% with the 400 pg/mL cut-off and by 28%–29% with the 300 pg/mL cut-off. This corresponded to a yearly cost reduction of approximately €2–5 million per million inhabitants in these counties.

    Conclusion. The use of NT-proBNP as a screening test could substantially reduce the number of echocardiographies in the diagnostic work-up of patients with suspected cardiac failure, as well as the associated costs.

  • 35.
    Fyrberg, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Kågedal, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells2011Inngår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 68, nr 3, s. 583-591Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To characterize resistance mechanisms to the nucleoside analog 9-β-D-arabinofuranosylguanine (AraG) in the T-cell acute lymphoblastic leukemia cell line MOLT-4 and its AraG-resistant variant.

    METHODS: A gene expression microarray analysis was performed, as well as gene expression and enzyme activity measurements of key enzymes in the activation of AraG. Cytotoxicity of AraG and cross-resistance to other compounds were evaluated using a standard cytotoxicity assay.

    RESULTS: Gene expression microarray analysis revealed that fetal hemoglobin genes and the multidrug resistance ABCB1 gene, encoding the drug efflux pump P-gp, were the most highly upregulated genes in the resistant cells, while genes traditionally associated with nucleoside analog resistance were not. Fetal hemoglobin and ABCB1 induction can be due to global DNA hypomethylation. This phenomenon was studied using AraG during a period of 4 weeks in MOLT-4 cells and the lung adenocarcinoma cell line A549, leading to up-regulation of hemoglobin gamma and ABCB1 as well as DNA hypomethylation. Inhibiting P-gp in the AraG-resistant MOLT-4 cells led to decreased proliferation, reduced hemoglobin expression, and highly induced ABCB1 expression.

    CONCLUSIONS: We show that AraG can cause hypomethylation of DNA and induce the expression of the fetal hemoglobin gamma gene and the ABCB1 gene. We speculate that the induction of ABCB1/P-gp may occur in order to help with excretion of hemoglobin degradation products that would otherwise be toxic to the cells, and we present data supporting our theory that P-gp may be linked to the induction of hemoglobin.

  • 36.
    Fälker, Knut
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Haglund, Linda
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Nylander, Martina
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Grenegård, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets2011Inngår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 436, s. 469-480Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    FARs (protease-activated receptors) 1 and 4 belong to the family of G-protein-coupled receptors which induce both G(alpha 12/13) and G(alpha q) signalling. By applying the specific PAR1- and PAR4-activating hexapeptides, SFLLRN and AYPGKF respectively, we found that aggregation of isolated human platelets mediated via PAR1, but not via PAR4, is abolished upon homologous receptor activation in a concentration- and time-dependent fashion. This effect was not due to receptor internalization, but to a decrease in Ca(2+) mobilization, PKC (protein kinase C) signalling and alpha-granule secretion, as well as to a complete lack of dense granule secretion. Interestingly, subthreshold PAR4 activation rapidly abrogated PAR1 signalling desensitization by differentially reconstituting these affected signalling events and functional responses, which was sufficient to re-establish aggregation. The lack of ADP release and P2Y(12) receptor-induced G(alpha i) signalling accounted for the loss of the aggregation response, as mimicking G(alpha i/z) signalling with 2-MeS-ADP (2-methylthioadenosine-5-O-diphosphate) or epinephrine (adrenaline) could substitute for intermediate PAR4 activation. Finally, we found that the re-sensitization of PAR1 signalling-induced aggregation via PAR4 relied on PKC-mediated release of both ADP from dense granules and fibrinogen from alpha-granules. The present study elucidates further differences in human platelet PAR signalling regulation and provides evidence for a cross-talk in which PAR4 signalling counteracts mechanisms involved in PAR1 signalling down-regulation.

  • 37.
    Fälker, Knut
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Klarstrom-Engstrom, Kristin
    University of Örebro, Sweden .
    Bengtsson, Torbjorn
    University of Örebro, Sweden .
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Grenegard, Magnus
    University of Örebro, Sweden .
    The Toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLC gamma 2 signalling cascade2014Inngår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 26, nr 2, s. 279-286Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The specific TLR2/1 complex activator Pam3CSK4 has been shown to provoke prominent activation and aggregation of human non-nucleated platelets. As Pam3CSK4-evoked platelet activation does not employ the major signalling pathway established in nucleated immune cells, we investigated if the TLR2/1 complex on platelets may initiate signalling pathways known to be induced by physiological agonists such as collagen via GPVI or thrombin via PARs. We found that triggering TLR2/1 complex-signalling with Pam3CSK4, in common with that induced via GPVI, and in contrast to that provoked by PARS, involves tyrosine phosphorylation of the adaptor protein LAT as well as of PLC gamma 2 in a src- and Syk-dependent manner. In this respect, we provide evidence that Pam3CSK4 does not cross-activate GPVI. Further, by the use of platelets from a Glanzmanns thrombasthenia patient lacking beta(3), in contrast to findings in nucleated immune cells, we show that the initiation of platelet activation by Pam3CSK4 does not involve integrin beta(3) signalling; whereas the latter, subsequent to intermediate TXA2 synthesis and signalling, was found to be indispensable for proper dense granule secretion and full platelet aggregation. Together, our findings reveal that triggering the TLR2/1 complex with Pam3CSK4 initiates human platelet activation by engaging tyrosine kinases of the src family and Syk, the adaptor protein LAT, as well as the key mediator PLC gamma 2.

  • 38.
    Georgiopoulos, Charalampos
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Davidsson, Anette
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk fysiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Fysiologiska kliniken US.
    Granerus, Göran
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk fysiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Fysiologiska kliniken US.
    Dizdar (Dizdar Segrell), Nil
    Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Zachrisson, Helene
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk fysiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Fysiologiska kliniken US.
    DaTSCAN SPECT EVALUATION OF PATIENTS WITH MOVEMENT DISORDERS2011Inngår i: EUROPEAN JOURNAL OF NEUROLOGY, Wiley-Blackwell, 2011, Vol. 18 (Suppl. 2), nr SI, s. 567-567, artikkel-id P2617Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    Introduction: Molecular imaging with DaTSCAN SPECTis widely used as a diagnostic tool in patients with movementdisorders in the form of Parkinson's Disease (PD),Parkinson-plus syndromes and Tremor. In the present studythe potency of DATScan SPECT to detect degeneration inthe basal ganglia in early stages of PD, before the onset ofmedication, is evaluated. In addition the efficacy ofDaTSCAN for differential diagnosis between patients withidiopathic PD and patients with Parkinson-plus syndromesis examined.

    Methodology: Participants: 21 patients with PD in earlystages, before the onset of medication, 20 patients withidiopathic PD and 6 patients with Parkinson-plussyndromes. 15 participants with normal results ofDaTSCAN SPECT and a clinical diagnosis different fromPD or Parkinson-plus were used as control.

    DaTSCAN SPECT: In the present study the quantificationof Striatum Occipital/Occipital and the Xeleris workstation(GE) were used.

    Results: The quantification for patients with idiopathic PD(1.185±0.05687) was significantly lower (p<0.0001) fromthe control (2.369±0.1258) and significantly lower (p<0.05)from that of patients in early stages of PD, before the onsetof medication (1.359±0.05324). There was no significantdifference between the idiopathic PD and Parkinson-plussyndromes (1.103±0.2442).

    Conclusion: DaTSCAN SPECT can detect efficiently earlydegeneration in the basal ganglia before the onset ofmedication is needed. Its efficacy for the differentialdiagnosis between idiopathic PD and Parkinson-plussyndromes is questioned. The combination of imaging andclinical examination is mandatory for a certain diagnosis.

  • 39.
    Grip, L
    et al.
    Karolinska Institute, Sweden .
    Lonne-Rahm, S-B
    Karolinska Institute, Sweden .
    Holst, M
    Astrid Lindgren Childrens Hospital, Sweden .
    Johansson, B
    Karolinska Institute, Sweden .
    Nordlind, K
    Karolinska Institute, Sweden .
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    El-Nour, H
    Karolinska Institute, Sweden .
    Substance P alterations in skin and brain of chronically stressed atopic-like mice2013Inngår i: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 27, nr 2, s. 199-205Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Stress is known to worsen the symptoms of atopic eczema (AE). Substance P is likely to play an important role in the development and pathogenesis of AE. less thanbrgreater than less thanbrgreater thanObjective To examine a possible connection between chronic mild stress and changes in the expression of substance P and its receptor (R) neurokinin (NK) 1 in the skin and stress-related brain regions in NC/Nga atopic-like mice. less thanbrgreater than less thanbrgreater thanMethods The mice were divided into three groups (eight animals per group): SE (stressed eczematous), NSE (non-stressed eczematous) and SC (stressed control). Ears and brains of the mice were investigated using immunohistochemistry and RT-PCR. less thanbrgreater than less thanbrgreater thanResults In the skin, there was a decrease in the number of substance P immunoreactive nerve fibres in SE compared with SC group. RT-PCR showed a strong tendency to an increase in mRNA for NK1R in the skin of SE compared with NSE mice. There was an increase in the number of mast cells and the degree of their degranulation in the SE compared with both other groups. less thanbrgreater than less thanbrgreater thanA decrease in substance P immunoreactivity in medial hippocampus was found in SE compared with NSE animals. In prefrontal cortex and central amygdala, there were no significant differences in substance P immunoreactivity between the three groups. less thanbrgreater than less thanbrgreater thanConclusion Exposure to chronic mild stress in NC/Nga atopic-like mice may result in altered expression patterns of substance P in the skin and hippocampus.

  • 40.
    Gréen, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Vretenbrandt, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Norlander, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Measurement of Paclitaxel and its metabolites in Human Plasma Using a Liquid Chromatography - Ion Trap Mass Spectrometer with a SSI interface2008Konferansepaper (Fagfellevurdert)
  • 41.
    Gurbel, Paul A.
    et al.
    Sinai Centre Thrombosis Research, MD 21215 USA.
    Bergmeijer, Thomas O.
    St Antonius Hospital, Netherlands.
    Tantry, Udaya S.
    Sinai Centre Thrombosis Research, MD 21215 USA.
    ten Berg, Jurrien M.
    St Antonius Hospital, Netherlands.
    Angiolillo, Dominick J.
    University of Florida, FL USA.
    James, Stefan
    Uppsala University, Sweden.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Svensson, Peter
    Lund University, Sweden.
    Jakubowski, Joseph A.
    Eli Lilly and Co, IN 46285 USA.
    Brown, Patricia B.
    Eli Lilly and Co, IN 46285 USA.
    Duvvuru, Suman
    Eli Lilly and Co, IN 46285 USA.
    Sundseth, Scott
    Cabernet Pharmaceut, NC USA.
    Walker, Joseph R.
    Daiichi Sankyo Pharma Dev, NJ USA.
    Small, David
    Eli Lilly and Co, IN 46285 USA.
    Moser, Brian A.
    Eli Lilly and Co, IN 46285 USA.
    Winters, Kenneth J.
    Eli Lilly and Co, IN 46285 USA.
    Erlinge, David
    Lund University, Sweden.
    The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease2014Inngår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, nr 3, s. 589-597Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC([0-tlast])), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC((0-tlast)) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [Cl]: 0.86,1.17, pgreater than0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, pless than0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures pless than0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons pless than0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all pless than0.001), and comparable effects in EMs (all p greater than= 0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.

  • 42.
    Gustafsson, Sofia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Liang, Wen
    TNO Metabolic Health Research, Leiden, The Netherlands.
    Hilke, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Effects of voluntary running in the female mice lateral septum on BDNF and corticotropin-releasing factor receptor 22011Inngår i: International Journal of Peptides, ISSN 1687-9767, E-ISSN 1687-9775, Vol. 2011, s. 932361-932366Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Voluntary physical activities are known to modulate anxiety and depressive/like behaviors in both animals and humans. Brain derived neurotrophic factor (BDNF), has been reported to be elevated following exercise. BDNF, as well as type 2 corticotrophin releasing factor receptor (CRFR) 2, has been shown to mediate anxiety-like behavior. In the present study we examined the effects of long-term voluntary exercise on the transcripts for BDNF and CRFR2 in the lateral septum (LS) and for CRF in the central amygdala (CeA) in female mice. Thus, increased activity of CRF in the CeA is associated with anxiety-like behavior. Quantitative RT-PCR was employed to measure levels of mRNA in punch biopsies from LS and CeA. In addition, measurements of the concentration of corticosterone and leptin in plasma were employed. In the LS, we found a three-fold increase of BDNF mRNA (P < 0.05) but no significant change in CRFR2 mRNA. No changes in CRF in the amygdala were observed but we found a decrease in the levels of plasma corticosterone. Plasma leptin and the weight of perigonadal fat pads were decreased following exercise. In conclusion, these data show that BDNF gene expression in the LS is influenced by long-term exercise in females but not CRFR2.

  • 43.
    Haarhaus, Mathias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Bone alkaline phosphatase isoforms in chronic kidney disease: mineral and bone disorder2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Chronic kidney disease (CKD) is associated with increased mortality and cardiovascular complications. Disturbances in mineral metabolism occur early <luring the course of CKD and several components of the CKD-mineral and bone disorder (CKD-MBD) are independent predictors of mortality. Alkaline phosphatase (ALP) is necessary for skeletal mineralization and is also involved in the process of vascular calcification. In recent years, ALP has evolved as a strong predictor of mortality in the CKD population. The significant role of ALP in the mineralization process renders it a putative target for the treatment and prevention of vascular calcification. Three circulating isoforms of bone ALP (BALP) have been identified (B/I, B 1, and B2). A fourth isoform, Blx, has been identified exclusively in serum from patients with CKD. The aim of the present thesis was to further elucidate the role ofthe BALP isoforms in CKD with respect to bone abnormalities and vascular calcification.

    In study I we identified the novel BALP isoform Blx in 20% of patients with mild to moderate CKD. Blx was associated with lower glomerular filtration rate and higher serum phosphate and calcium x phosphate product, which are risk factors for cardiovascular mortality in CKD. We also identified the BALP isoforms B/I, Bl and B2 as predictors of total hip bone mineral density.

    Study II was an experimental study, investigating the role of the BALP isoforms in phosphate induced calcification of human aortic smooth muscle cells (HASMCs). We found that the ALP expressed in HASMCs is exclusively BALP. Phosphate induced calcification of HASMCs was associated with increased BALP isoforms B/I, Blx, and B2 activities, which implies functional differences between the BALP isoforms in HASMC calcification.

    In study III we investigated the association of BALP isoforms in serum and histomorphometric parameters of bone in patients on chronic hemodialysis. W e identified the BALP isoform Blx as a novel marker for reduced osteoblastic activity.

    Study IV was a prospective cohort study of the association of serum BALP isoforms with aortic calcification and vascular stiffness in prevalent chronic dialysis patients. Blx was associated with baseline and time varying vascular stiffness, determined by pulse wave velocity, but not with calcification of the abdominal aorta. We also found an association of Blx with better event-free survival.

    In conclusion, these studies demonstrate that the BALP isoforms, especially isoform Blx, are involved in different aspects of CKD-MBD. This opens up for further research to identify the BALP isoforms as diagnostic markers and possible treatment targets in CKD-MBD.

    Delarbeid
    1. Clinical significance of bone alkaline phosphatase isoforms, including the novel B1x isoform, in mild to moderate chronic kidney disease
    Åpne denne publikasjonen i ny fane eller vindu >>Clinical significance of bone alkaline phosphatase isoforms, including the novel B1x isoform, in mild to moderate chronic kidney disease
    2009 (engelsk)Inngår i: NEPHROLOGY DIALYSIS TRANSPLANTATION, ISSN 0931-0509, Vol. 24, nr 11, s. 3382-3389Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background. Mineral bone disorder (MBD) is a common complication of chronic kidney disease (CKD) even during the early stages. Bone alkaline phosphatase (BALP) is a marker of bone fort-nation and plays a pivotal role in the mineralization process. Three BALP isoforms (B/I, B1 and B2) have been identified in healthy individuals and a fourth isoform (B1x) has been discovered in serum from dialysis patients. We investigated these BALP isoforms, type I procollagen intact amino-terminal propeptide (PINP), carboxy-terminal telopeptide of type I collagen (CTX) and tartrate-resistant acid phosphatase isoform 5b (TRACP5b), as well as bone mineral density (BMD) in predialysis CKD patients. Methods. PINP, CTX, TRACP5b and BALP isoforms were analysed in serum from 46 patients within CKD stages 3-5. BMD was determined by dual-energy x-ray absorptiometry. Results. PINP, TRACP5b and the BALP isoforms, B/I, B1 and B2, were independent predictors of total hip BMD in all patients. Furthermore, B/I predicted osteopaenia in the hip and in the distal 1/3 of the radius in CKD stage 3. The B1x isoform was detected in nine patients (20%), who had lower GFR, higher phosphate and calcium x phosphate product. Conclusion. We found an association of BALP isoforms and other markers of bone turnover with total hip BMD, which predominantly comprises trabecular bone. The association of the new BALP isoform B1x with risk factors for vascular calcification leads us to hypothesize a possible role for B1x in this process. The significance of the BALP isoforms in CKD remains to be further explored in experimental and clinical settings in conjunction with bone histomorphometry.

    Emneord
    alkaline phosphatase, bone mineral density, bone turnover, mineral bone disorder, predialysis
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-52373 (URN)10.1093/ndt/gfp300 (DOI)
    Tilgjengelig fra: 2009-12-18 Laget: 2009-12-18 Sist oppdatert: 2014-11-06
    2. Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform
    Åpne denne publikasjonen i ny fane eller vindu >>Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform
    2013 (engelsk)Inngår i: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 50, nr 2, s. 167-174Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Vascular calcification, causing cardiovascular morbidity and mortality, is associated with hyperphosphatemia in chronic kidney disease (CKD). In vitro, phosphate induces transdifferentiation of vascular smooth muscle cells to osteoblast-like cells that express alkaline phosphatase (ALP). In vivo, raised serum ALP activities are associated with increased mortality. A new bone ALP isoform (B1x) has been identified in serum from CKD patients. The present study investigated the different ALP isoforms in calcifying human aortic smooth muscle cells (HAoSMCs). Methods: HAoSMCs were cultured for 30 days in medium containing 5 or 10 mmol/l beta-glycerophosphate in the presence or absence of the ALP-specific inhibitor tetramisole. Results: All known bone-specific ALP (BALP) isoforms (B/I, B1x, B1 and B2) were identified in HAoSMCs. beta-Glycerophosphate stimulated calcification of HAoSMCs, which was associated with increased BALP isoforms B/I, B1x and B2. Tetramisole inhibited the beta-glycerophosphate-induced HAoSMC calcification, which was paralleled by the inhibition of the B1x and B/I, but not the other isoforms. Conclusions: HAoSMCs express the four known BALP isoforms. B/I, B1x and B2 could be essential for soft tissue calcification. B/I and B1x were more affected by tetramisole than the other isoforms, which suggests different biological functions during calcification of HAoSMCs.

    sted, utgiver, år, opplag, sider
    S. Karger, 2013
    Emneord
    Bone-specific alkaline phosphatase, Chronic kidney disease, Human aortic smooth muscle cells, Isoforms, Phosphate, Vascular calcification
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-90089 (URN)10.1159/000346161 (DOI)000314995500008 ()
    Merknad

    Funding Agencies|Ingrid Asps Foundation for Nephrology Research at Linkoping University||County Council of Ostergotland||Swedish Association for Kidney Patients||

    Tilgjengelig fra: 2013-03-21 Laget: 2013-03-19 Sist oppdatert: 2017-12-06
    3. Bone alkaline phosphatase isoforms in CKD patients on hemodialysis with low and high bone turnover
    Åpne denne publikasjonen i ny fane eller vindu >>Bone alkaline phosphatase isoforms in CKD patients on hemodialysis with low and high bone turnover
    2014 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (BALP) isoform B1x is exclusively found in serum of some CKD patients.

    Study Design: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum BALP isoform activities and histomorphometric parameters of bone in patients with CKD on chronic hemodialysis.

    Setting & Participants: Anterior iliac crest bone biopsy samples from 40 CKD patients were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover.

    Index Test: In serum, BALP, BALP isoforms (B/I, B1x, B1 and B2), and parathyroid hormone (PTH) were measured.

    Reference Test or Outcome: Indices of osteoblastic activity and number.

    Other Measurements: Parathyroid hormone

    Results: B1x was found in 21 patients (53%) who had lower median levels of BALP, 18.6 versus 46.9 U/L; B/I, 0.10 versus 0.22 μkat/L; B1, 0.40 versus 0.88 μkat/L; B2, 1.21 versus 2.66 μkat/L; and PTH, 49 versus 287 pg/mL, compared to patients without B1x (p<0.001). B1x correlated inversely with osteoblast number and activity. ROC curves showed that B1x (AUC 0.83) can be used for diagnosis of low osteoblastic activity, while BALP (AUC 0.78) and PTH (AUC 0.77) are useful for diagnosis of high osteoblast number seen with high bone turnover.

    Limitations: Small number of study participants.

    Conclusions: The presence of B1x in serum may be a sign of perturbed osteoblast activity and it may be useful as a diagnostic parameter for low bone turnover rate.

    Emneord
    Bone-specific alkaline phosphatase; isoforms; renal osteodystrophy; osteoblast activity; low bone turnover
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-111868 (URN)
    Tilgjengelig fra: 2014-11-06 Laget: 2014-11-06 Sist oppdatert: 2015-03-31bibliografisk kontrollert
    4. A multicenter prospective study of bone alkaline phosphatase isoforms and arterial calcification in chronic kidney disease patients on dialysis
    Åpne denne publikasjonen i ny fane eller vindu >>A multicenter prospective study of bone alkaline phosphatase isoforms and arterial calcification in chronic kidney disease patients on dialysis
    2014 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Chronic kidney disease – mineral and bone disorder (CKD-MBD) is associated with high morbidity and mortality due to frequent cardiovascular (CV) complications. Accelerated arterial stiffening and calcification are associated with serum alkaline phosphatase (ALP) in advanced CKD. We have previously described three bone ALP (BALP) isoforms in healthy individuals and detected a novel isoform, B1x, exclusively in serum from some CKD patients, in bone and in calcifying vascular smooth muscle cells. We investigated the association of these BALP isoforms, abdominal aortic calcification (AAC) score and carotid – femoral pulse wave velocity (PWV), with outcome in a 2-year prospective multicenter study of 68 prevalent dialysis patients participating in the Calcification Outcome in Renal Disease (CORD) study. Twenty-one patients experienced a combined event of all-cause mortality or a first nonfatal CV event during follow-up. PWV (hazard ratio 1.067, P = 0.03) was independently associated with the combined event. B1x was detected in 53 patients and was associated with baseline PWV (Kendall's tau 0.23, P = 0.007) and with variation of PWV over time (estimate 14.14, P = 0.03). Patients with B1x had lower levels of PTH and total ALP, indicating a possible association with low bone turnover. We found no association of BALP isoforms with AAC score. Cox regression revealed B1x as a positive predictor of event free survival (hazard ratio 0.98, P = 0.01). In conclusion, B1x is associated with vascular stiffness in CKD 5D. This finding is contrasted by the ability of B1x to predict longer event free survival in the current study.

    Emneord
    Chronic kidney disease – mineral and bone disorder, dialysis, bone alkaline phosphatase, mortality, cardiovascular disease
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-111869 (URN)
    Tilgjengelig fra: 2014-11-06 Laget: 2014-11-06 Sist oppdatert: 2015-03-31bibliografisk kontrollert
  • 44.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Njurmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Arnqvist, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrinmedicinska enheten.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform2013Inngår i: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 50, nr 2, s. 167-174Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Vascular calcification, causing cardiovascular morbidity and mortality, is associated with hyperphosphatemia in chronic kidney disease (CKD). In vitro, phosphate induces transdifferentiation of vascular smooth muscle cells to osteoblast-like cells that express alkaline phosphatase (ALP). In vivo, raised serum ALP activities are associated with increased mortality. A new bone ALP isoform (B1x) has been identified in serum from CKD patients. The present study investigated the different ALP isoforms in calcifying human aortic smooth muscle cells (HAoSMCs). Methods: HAoSMCs were cultured for 30 days in medium containing 5 or 10 mmol/l beta-glycerophosphate in the presence or absence of the ALP-specific inhibitor tetramisole. Results: All known bone-specific ALP (BALP) isoforms (B/I, B1x, B1 and B2) were identified in HAoSMCs. beta-Glycerophosphate stimulated calcification of HAoSMCs, which was associated with increased BALP isoforms B/I, B1x and B2. Tetramisole inhibited the beta-glycerophosphate-induced HAoSMC calcification, which was paralleled by the inhibition of the B1x and B/I, but not the other isoforms. Conclusions: HAoSMCs express the four known BALP isoforms. B/I, B1x and B2 could be essential for soft tissue calcification. B/I and B1x were more affected by tetramisole than the other isoforms, which suggests different biological functions during calcification of HAoSMCs.

  • 45.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden.
    Fernström, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    A multicenter prospective study of bone alkaline phosphatase isoforms and arterial calcification in chronic kidney disease patients on dialysis2014Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Chronic kidney disease – mineral and bone disorder (CKD-MBD) is associated with high morbidity and mortality due to frequent cardiovascular (CV) complications. Accelerated arterial stiffening and calcification are associated with serum alkaline phosphatase (ALP) in advanced CKD. We have previously described three bone ALP (BALP) isoforms in healthy individuals and detected a novel isoform, B1x, exclusively in serum from some CKD patients, in bone and in calcifying vascular smooth muscle cells. We investigated the association of these BALP isoforms, abdominal aortic calcification (AAC) score and carotid – femoral pulse wave velocity (PWV), with outcome in a 2-year prospective multicenter study of 68 prevalent dialysis patients participating in the Calcification Outcome in Renal Disease (CORD) study. Twenty-one patients experienced a combined event of all-cause mortality or a first nonfatal CV event during follow-up. PWV (hazard ratio 1.067, P = 0.03) was independently associated with the combined event. B1x was detected in 53 patients and was associated with baseline PWV (Kendall's tau 0.23, P = 0.007) and with variation of PWV over time (estimate 14.14, P = 0.03). Patients with B1x had lower levels of PTH and total ALP, indicating a possible association with low bone turnover. We found no association of BALP isoforms with AAC score. Cox regression revealed B1x as a positive predictor of event free survival (hazard ratio 0.98, P = 0.01). In conclusion, B1x is associated with vascular stiffness in CKD 5D. This finding is contrasted by the ability of B1x to predict longer event free survival in the current study.

  • 46.
    Haarhaus, Mathias
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden.
    Monier-Faugere, Marie-Claude
    Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    Malluche, Hartmut H.
    Bone alkaline phosphatase isoforms in CKD patients on hemodialysis with low and high bone turnover2014Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (BALP) isoform B1x is exclusively found in serum of some CKD patients.

    Study Design: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum BALP isoform activities and histomorphometric parameters of bone in patients with CKD on chronic hemodialysis.

    Setting & Participants: Anterior iliac crest bone biopsy samples from 40 CKD patients were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover.

    Index Test: In serum, BALP, BALP isoforms (B/I, B1x, B1 and B2), and parathyroid hormone (PTH) were measured.

    Reference Test or Outcome: Indices of osteoblastic activity and number.

    Other Measurements: Parathyroid hormone

    Results: B1x was found in 21 patients (53%) who had lower median levels of BALP, 18.6 versus 46.9 U/L; B/I, 0.10 versus 0.22 μkat/L; B1, 0.40 versus 0.88 μkat/L; B2, 1.21 versus 2.66 μkat/L; and PTH, 49 versus 287 pg/mL, compared to patients without B1x (p<0.001). B1x correlated inversely with osteoblast number and activity. ROC curves showed that B1x (AUC 0.83) can be used for diagnosis of low osteoblastic activity, while BALP (AUC 0.78) and PTH (AUC 0.77) are useful for diagnosis of high osteoblast number seen with high bone turnover.

    Limitations: Small number of study participants.

    Conclusions: The presence of B1x in serum may be a sign of perturbed osteoblast activity and it may be useful as a diagnostic parameter for low bone turnover rate.

  • 47.
    Halling Linder, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Enander, Karin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Glycation Contributes to Interaction Between Human Bone Alkaline Phosphatase and Collagen Type I2016Inngår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 98, nr 3, s. 284-293Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bone is a biological composite material comprised primarily of collagen type I and mineral crystals of calcium and phosphate in the form of hydroxyapatite (HA), which together provide its mechanical properties. Bone alkaline phosphatase (ALP), produced by osteoblasts, plays a pivotal role in the mineralization process. Affinity contacts between collagen, mainly type II, and the crown domain of various ALP isozymes were reported in a few in vitro studies in the 1980s and 1990s, but have not attracted much attention since, although such interactions may have important implications for the bone mineralization process. The objective of this study was to investigate the binding properties of human collagen type I to human bone ALP, including the two bone ALP isoforms B1 and B2. ALP from human liver, human placenta and E. coli were also studied. A surface plasmon resonance-based analysis, supported by electrophoresis and blotting, showed that bone ALP binds stronger to collagen type I in comparison with ALPs expressed in non-mineralizing tissues. Further, the B2 isoform binds significantly stronger to collagen type I in comparison with the B1 isoform. Human bone and liver ALP (with identical amino acid composition) displayed pronounced differences in binding, revealing that post-translational glycosylation properties govern these interactions to a large extent. In conclusion, this study presents the first evidence that glycosylation differences in human ALPs are of crucial importance for protein–protein interactions with collagen type I, although the presence of the ALP crown domain may also be necessary. Different binding affinities among the bone ALP isoforms may influence the mineral-collagen interface, mineralization kinetics, and degree of bone matrix mineralization, which are important factors determining the material properties of bone.

  • 48.
    Hillarp, A.
    et al.
    University and Regional Laboratories Region Skåne, Malmö, Sweden.
    Gustafsson, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Faxälv, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Strandberg, K.
    University and Regional Laboratories Region Skåne, Malmö, Sweden.
    Baghaei, F.
    Sahlgrenska University Hospital, Sweden; University of Gothenburg, Sweden.
    Fagerberg Blixter, I.
    Sahlgrenska University Hospital, Sweden; University of Gothenburg, Sweden.
    Berndtsson, M.
    Karolinska University Hospital, Stockholm, Sweden.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays2014Inngår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, nr 9, s. 1545-1553Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION:

    Apixaban is an oral direct factor Xa inhibitor developed for the prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary, but the effects on common coagulation reagents and assays constitute clinically valuable information.

    OBJECTIVES:

    To investigate the effects of apixaban on commonly used coagulation methods, and to evaluate anti-FXa assays for specific determination of the drug concentration.

    MATERIALS AND METHODS:

    Apixaban was added to plasma from healthy subjects in the concentration range 0-1000 μg L(-1) , and analyses were performed with different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, protein C, and protein S. A lupus anticoagulant assay and an APTT assay with varying phospholipid concentrations were used to study the phospholipid dependence.

    RESULTS:

    In general, apixaban showed fewer effects in vitro than have been shown for rivaroxaban, another direct FXa inhibitor. The concentration needed to double the APTT varied between 2200 and 4700 μg L(-1) , and the concentration needed to double the PT varied between 700 and 3900 μg L(-1) . The effects on antithrombin, protein C and protein S assays were dependent on the type of reagent. Apixaban did not cause false-positive lupus anticoagulant results. Chromogenic anti-FXa assays showed linear dose-response curves with apixaban.

    CONCLUSIONS:

    Therapeutic concentrations of apixaban variably affect different assay groups, and even different reagents within an assay group. The effects were much smaller than with rivaroxaban. The use of APTT and/or PT assays to screen the anticoagulant activity of apixaban cannot be recommended. A chromogenic anti-FXa assay can be used for reliable measurements of apixaban concentration.

  • 49.
    Holm, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Hilke, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Hokfelt, Tomas
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Theodorsson, Annette
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Neurokirurgiska kliniken US.
    Changes in galanin and GalR1 gene expression in discrete brain regions after transient occlusion of the middle cerebral artery in female rats2012Inngår i: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 46, nr 1, s. 19-27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Injury to neurons results in upregulation of galanin in some central and peripheral systems, and it has been suggested that this neuropeptide may play a protective and trophic role, primarily mediated by galanin receptor 2 (GalR2). The objective of the present study was to investigate galanin, GalR1, GalR2 and GalR3 gene expression in the female rat brain seven days after a 60-min unilateral occlusion of the middle cerebral artery followed by reperfusion. Quantitative real-time PCR was employed in punch-biopsies from the locus coeruleus, somatosensory cortex and dorsal hippocampal formation including sham-operated rats as controls. Galanin gene expression showed a ~2.5-fold increase and GalR1 a ~1.5-fold increase in the locus coeruleus of the ischemic hemisphere compared to the control side. Furthermore, the GalR1 mRNA levels decreased by 35% in the cortex of the ischemic hemisphere. The present results indicate that a stroke-induced forebrain lesion upregulates synthesis of galanin and GalR1 in the locus coeruleus, a noradrenergic cell group projecting to many forebrain areas, including cortex and the hippocampal formation. These results support the notion that galanin may play a role in the response of the central nervous system to injury and have trophic eff ects.

  • 50.
    Holm, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Liang, Wen
    TNO Metabolic Health Research, Leiden, Netherlands.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hilke, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Acute effects on brain cholecystokinin-like concentration and anxiety-like behaviour in the female rat upon a single injection of 17β-estradiol2014Inngår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 122, s. 222-227Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The neuropeptide cholecystokinin (CCK) has been implicated in the neurobiology of anxiety and panic disorders, as well as in dopamine-related behaviours. Anxiety and panic-disorders are twice as common in females compared to males, but studies of females are rare, although increasing in number. Limited studies have found that CCK fluctuates in limbic regions during the estrous cycle, and that CCK and its receptors are sensitive to estrogen.

    AIM/PURPOSE: The aim of the present work was to study the acute effects of 17β-estradiol on anxiety-like behaviour and on CCK-like immunoreactivity (LI) in the female rat brain (amygdala, hippocampus, nucleus accumbens, and cingulate cortex).

    METHODS: Four groups of female Sprague-Dawley rats were used: ovariectomized, ovariectomized+17β-estradiol-replacement, sham, and sham+17β-estradiol-replacement. The effect of 17β-estradiol-replacement on anxiety-related behaviour was measured in all animals on the elevated plus maze 2-24h after injection. CCK-LI concentration was measured in punch biopsies by means of radioimmunoassay.

    RESULTS: 17β-estradiol decreased anxiety-like behaviour 2h after administration in ovariectomized and sham-operated animals, as demonstrated by increased exploration of the open arms compared to respective sesame oil-treated controls. This effect was not present when testing occurred 24h post-treatment. The rapid behavioural effect of 17β-estradiol was accompanied by changes in CCK-LI concentrations in regions of the limbic system including cingulate cortex, hippocampus, amygdala and nucleus accumbens.

    CONCLUSION: Although the interpretation of these data requires caution since the data were collected from two different experiments, our results suggest that estrogen-induced anxiolytic effects may be associated with changes of the CCK-system in brain regions controlling anxiety-like behaviour.

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