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Now showing items 176-192 of 192
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Vonen, Barthold; Augestad, Knut M; Aspevik, Ranveig; Norum, Jan; Nestvold, Torunn; Lindsetmo, Rolv-Ole; Ringberg, Unni; Johnsen, Roar (Journal article; Tidsskriftartikkel, 25-Jun-2008)[+][-]
Abstract: Background: All patients who undergo surgery for colon cancer are followed up according to the guidelines of the Norwegian Gastrointestinal Cancer Group (NGICG). These guidelines state that the aims of follow-up after surgery are to perform quality assessment, provide support and improve survival. In Norway, most of these patients are followed up in a hospital setting. We describe a multi-centre randomized controlled trial to test whether these patients can be followed up by their general practitioner (GP) without altering quality of life, cost effectiveness and/or the incidence of serious clinical events.
Methods and Design: Patients undergoing surgery for colon cancer with histological grade Dukes's Stage A, B or C and below 75 years of age are eligible for inclusion. They will be randomized after surgery to follow-up at the surgical outpatient clinic (control group) or followup by the district GP (intervention group). Both study arms comply with the national NGICG guidelines. The primary endpoints will be quality of life (QoL) (measured by the EORTC QLQ C- 30 and the EQ-5D instruments), serious clinical events (SCEs), and costs. The follow-up period will be two years after surgery, and quality of life will be measured every three months. SCEs and costs will be estimated prospectively. The sample size was 170 patients.
Discussion: There is an ongoing debate on the best method of follow-up for patients with CRC. Due to a wide range of follow-up programmes and paucity of randomized trials, it is impossible to draw conclusions about the best combination and frequency of clinic (or family practice) visits, blood tests, endoscopic procedures and radiological examinations that maximize the clinical outcome, quality of life and costs. Most studies on follow-up of CRC patients have been performed in a hospital outpatient setting. We hypothesize that postoperative follow-up of colon cancer patients (according to national guidelines) by GPs will not have any impact on patients' quality of life. Furthermore, we hypothesize that there will be no increase in SCEs and that the incremental cost-effectiveness ratio will improve.
Trial registration: This trial has been registered at ClinicalTrials.gov. The trial registration number is: NCT00572143URI: http://hdl.handle.net/10037/2145 File(s) in this item: 1
article.pdf (294.1Kb) -
Vyas, HV; Eidem, BW; Cetta, F; Acharya, Ganesh; Huhta, J.; Roberson, D; Cuneo, B (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: Tissue Doppler Imaging (TDI) is a sensitive index of myocardial function. Its role in the fetus has not been extensively evaluated. To compare myocardial tissue Doppler velocities in fetuses with hypoplastic left heart syndrome (HLHS) to those of normal fetuses (matched for gestational age.) Cross-sectional retrospective study conducted at 2 large perinatal centers (2003-2007). Fetuses with HLHS ( n = 13) were compared with normal fetuses ( n = 207) in 5 gestational age groups. TDI data included peak systolic (s'), peak early (e'), and late diastolic velocities (a'). Linear regression was used to compare TDI parameters in fetuses with HLHS to normal fetuses matched for gestational age. Fetuses with HLHS had significantly reduced lateral tricuspid annular e' as compared to normal fetuses. Both normal fetuses and those with HLHS had linear increase in TDI velocities with advancing gestational age. TDI velocities are abnormal in fetuses with HLHS. TDI can be useful in serial follow-up of cardiac function in fetuses with HLHS. URI: http://hdl.handle.net/10037/3957 File(s) in this item: 1
article.pdf (346.2Kb) -
Wangberg, Silje C; Nilsen, Olav; Antypas, Konstantinos; Gram, Inger Torhild (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: Studies suggest that tailored materials are superior to nontailored materials in supporting health behavioral change. Several trials on tailored Internet-based interventions for smoking cessation have shown good effects. There have, however, been few attempts to isolate the effect of the tailoring component of an Internet-based intervention for smoking cessation and to compare it with the effectiveness of the other components. The study aim was to isolate the effect of tailored emails in an Internet-based intervention for smoking cessation by comparing two versions of the intervention, with and without tailored content. We conducted a two-arm, randomized controlled trial of the open and free Norwegian 12-month follow-up, fully automated Internet-based intervention for smoking cessation, slutta.no. We collected information online on demographics, smoking, self-efficacy, use of the website, and participant evaluation at enrollment and subsequently at 1, 3, and 12 months. Altogether, 2298 self-selected participants aged 16 years or older registered at the website between August 15, 2006 and December 7, 2007 and were randomly assigned to either a multicomponent, nontailored Internet-based intervention for smoking cessation (control) or a version of the same Internet-based intervention with tailored content delivered on the website and via email. Of the randomly assigned participants, 116 (of 419, response rate = 27.7%) in the intervention group and 128 (of 428, response rate = 29.9%) in the control group had participated over the 12 months and responded at the end of follow-up. The 7-day intention-to-treat abstinence rate at 1 month was 15.2% (149/982) among those receiving the tailored intervention, compared with 9.4% (94/999) among those who received the nontailored intervention (P < .001). The corresponding figures at 3 months were 13.5% (122/902) and 9.4% (84/896, P =.006) and at 12 months were 11.2% (47/419) and 11.7% (50/428, P = .91). Likewise, the intervention group had higher self-efficacy and perceived tailoring at 1 and 3 months. Self-efficacy was found to partially mediate the effect of the intervention. Tailoring an Internet-based intervention for smoking cessation seems to increase the success rates in the short term, but not in the long term. URI: http://hdl.handle.net/10037/3768 File(s) in this item: 1
article.pdf (464.2Kb) -
Wisborg, Torben; Montshiwa, Thapelo; Mock, Charles (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: Trauma is a major - and increasing - cause of death, especially in low- and middle income countries. In all countries rural areas are especially hard hit, and the distribution of physicians is skewed towards cities. To reduce avoidable deaths from injury all links in the chain of survival after trauma needs strengthening. Prioritizing in each country should be done by local researchers, but little research on injuries emerges from low- and middle income countries. Researchers in these countries need support and collaboration from their peers in industrialized countries. This partnership will be of mutual benefice. URI: http://hdl.handle.net/10037/3958 File(s) in this item: 1
article.pdf (726.2Kb) -
Hjortdahl, Magnus; Wisborg, Torben; Ringen, Amund H; Næss, Anne Cathrine Braarud (Journal article; Tidsskriftartikkel; Peer reviewed, 2009)[+][-]
Abstract: Background: Trauma is the leading cause of death for young people in Norway. Studies indicate that several of these deaths are avoidable if the patient receives correct initial treatment. The trauma team is responsible for initial hospital treatment of traumatized patients, and team members have previously reported that non-technical skills as communication, leadership and cooperation are the major challenges. Better team function could improve patient outcome. The aim of this study was to obtain a deeper understanding of which non-technical skills are important to members of the trauma team during initial examination and treatment of trauma patients. Methods: Twelve semi-structured interviews were conducted at four different hospitals of various sizes and with different trauma load. At each hospital a nurse, an anaesthesiologist and a team leader (surgeon) were interviewed. The conversations were transcribed and analyzed using systematic text condensation according to the principles of Giorgi's phenomenological analysis as modified by Malterud. Results and conclusion: Leadership was perceived as an essential component in trauma management. The ideal leader should be an experienced surgeon, have extensive knowledge of trauma care, communicate clearly and radiate confidence. Team leaders were reported to have little trauma experience, and the team leaders interviewed requested more guidance and supervision. The need for better training of trauma teams and especially team leaders requires further investigation and action. URI: http://hdl.handle.net/10037/3278 File(s) in this item: 1
article.pdf (208.3Kb) -
Wootton, Richard; Bonnardot, Laurent; Geissbuhler, Antoine; Jethwani, Kamal; Kovarik, Carrie; McGoey, Suzanne T.; Person, Donald; Vladzymyrskyy, Anton; Zolfo, Maria (Journal article; Tidsskriftartikkel; Peer reviewed, 2012)[+][-]
Abstract: Telemedicine networks, which deliver humanitarian services, sometimes need to share expertise to find particular experts in other networks. It has been suggested that a mechanism for sharing expertise between networks (a ‘clearing house’) might be useful. To propose a mechanism for implementing the clearing house concept for sharing expertise, and to confirm its feasibility in terms of acceptability to the relevant networks. We conducted a needs analysis among eight telemedicine networks delivering humanitarian services. A small proportion of consultations (5-10%) suggested that networks may experience difficulties in finding the right specialists from within their own resources. With the assistance of key stakeholders, many of whom were network coordinators, various methods of implementing a clearing house were considered. One simple solution is to establish a central database holding information about consultants who have agreed to provide help to other networks; this database could be made available to network coordinators who need a specialist when none was available in their own network. The proposed solution was examined in a desktop simulation exercise, which confirmed its feasibility and probable value. This analysis informs full-scale implementation of a clearing house, and an associated examination of its costs and benefits. URI: http://hdl.handle.net/10037/4930 File(s) in this item: 1
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Wynn, Rolf; Høiseth, Marita; Pettersen, Gunn (Journal article; Tidsskriftartikkel; Peer reviewed, 2012)[+][-]
Abstract: Prior research on psychopathy has primarily focused on the problem in men. Only a few studies have examined whether psychopathy even exists in women, and if so, how the disorder manifests itself in them. This paper presents a narrative review of the literature on gender and psychopathy. We briefly discuss why this is an important topic for women and we discuss its causes. The concept of psychopathy is defined and related to the diagnostic systems. The discussion includes a presentation of diagnostic tools, including the Hare Psychology Checklist – Revised, which are examined in relationship to the importance of biological gender. While emphasizing the similarities as well as the differences between the sexes, we discuss the matters of prevalence, behavioral expressions, comorbidity, progression, and treatment of the disorder. URI: http://hdl.handle.net/10037/4777 File(s) in this item: 1
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Andreassen, Hege K.; Wynn, Rolf; Bujnowska-Fedak, Maria M.; Chronaki, Catherine E.; Dumitru, Roxana C.; Pudule, Iveta; Santana, Silvina; Voss, Henning (Journal article; Tidsskriftartikkel; Peer reviewed, 10-Apr-2007)[+][-]
Abstract: Background: European citizens are increasingly being offered Internet health services. This study investigated patterns of health-related Internet use, its consequences, and citizens' expectations about their doctors' provision of e-health services. Methods: Representative samples were obtained from the general populations in Norway, Denmark, Germany, Greece, Poland, Portugal and Latvia. The total sample consisted of 7934 respondents. Interviews were conducted by telephone. Results: 44 % of the total sample, 71 % of the Internet users, had used the Internet for health purposes. Factors that positively affected the use of Internet for health purposes were youth, higher education, white-collar or no paid job, visits to the GP during the past year, long-term illness or disabilities, and a subjective assessment of one's own health as good. Women were the most active health users among those who were online. One in four of the respondents used the Internet to prepare for or follow up doctors' appointments. Feeling reassured after using the Internet for health purposes was twice as common as experiencing anxieties. When choosing a new doctor, more than a third of the sample rated the provision of e-health services as important. Conclusion: The users of Internet health services differ from the general population when it comes to health and demographic variables. The most common way to use the Internet in health matters is to read information, second comes using the net to decide whether to see a doctor and to prepare for and follow up on doctors' appointments. Hence, health-related use of the Internet does affect patients' use of other health services, but it would appear to supplement rather than to replace other health services. URI: http://hdl.handle.net/10037/1257 File(s) in this item: 1
article.pdf (254.1Kb) -
Wærhaug, Kristine; Langbakk, Bodil; Kuklin, Vladimir N.; Kirov, Mikhail Y.; Sovershaev, Mikhail; Ingebretsen, Ole C.; Ytrehus, Kirsti; Bjertnæs, Lars J. (Journal article; Tidsskriftartikkel; Peer reviewed, 15-Aug-2008)[+][-]
Abstract: Introduction: Acute lung injury often complicates severe sepsis. In Gram-negative sepsis, bacterial endotoxin activates both coagulation and inflammation. Enhanced lung vascular pressures and permeability, increased extravascular lung water content and deteriorated gas exchange characterize ovine endotoxin-induced lung injury, a frequently used model of acute lung injury. Recombinant human activated protein C (rhAPC), with its anticoagulant, anti-inflammatory, fibrinolytic and antiapoptotic effects, reportedly reduces the respiratordependent days and the mortality of patients with severe sepsis. We speculate whether rhAPC antagonizes endotoxin-induced lung injury in sheep.
Methods: Two groups of sheep were exposed to Escherichia coli endotoxin (lipopolysaccharide) 15 ng/kg/minute intravenously from 0 to 24 hours; one group received only lipopolysaccharide throughout (n = 8), and the other group received lipopolysaccharide in combination with rhAPC 24 μg/ kg/hour from 4 to 24 hours (n = 9). In addition, one group received rhAPC as above as the only intervention (n = 4), and four sham-operated sheep were used for determination of the α and ε isoforms of protein kinase C in pulmonary tissue. Data were assessed by one-way analysis of variance for repeated measurements. Biochemical data were analyzed using Student's t test, or using the Mann–Whitney U test when appropriate.
Results: Infusion of endotoxin caused lung injury, manifested by increments in pulmonary artery pressure, in pulmonary microocclusion pressure, in pulmonary vascular downstream resistance, in pulmonary vascular permeability index, in extravascular lung water index and in deterioration of oxygenation that were all attenuated by infusion of rhAPC. Endotoxemia led to changes in inflammation and coagulation, including pulmonary neutrophil accumulation paralleled by increased TNFα and decreased protein C and fibrinogen in animal plasma, which all improved following infusion of rhAPC. Moreover, rhAPC prevented the translocation of protein kinase C α and ε isoforms from the cytosolic fraction of lung tissue extracts.
Conclusion: In awake sheep, rhAPC alleviates endotoxininduced lung injury – as characterized by improvements of oxygenation, coagulation and inflammation, as well as by reversal of pulmonary hemodynamic and volumetric changes.URI: http://hdl.handle.net/10037/2172 File(s) in this item: 1
article.pdf (1.087Mb) -
Wærhaug, Kristine; Kirov, Mikhail Y.; Kuzkov, Vsevolod V.; Kuklin, Vladimir N.; Bjertnæs, Lars J. (Journal article; Tidsskriftartikkel; Peer reviewed, 20-Nov-2008)[+][-]
Abstract: Introduction: Acute lung injury (ALI) may arise both after sepsis and non-septic inflammatory conditions and is often associated with the release of fatty acids, including oleic acid (OA). Infusion of OA has been used extensively to mimic ALI. Recent research has revealed that intravenously administered recombinant human activated protein C (rhAPC) is able to counteract ALI. Our aim was to find out whether rhAPC dampens OA-induced ALI in sheep.
Methods: Twenty-two yearling sheep underwent instrumentation. After 2 days of recovery, animals were randomly assigned to one of three groups: (a) an OA+rhAPC group (n = 8) receiving OA 0.06 mL/kg infused over the course of 30 minutes in parallel with an intravenous infusion of rhAPC 24 mg/kg per hour over the course of 2 hours, (b) an OA group (n = 8) receiving OA as above, or (c) a sham-operated group (n = 6). After 2 hours, sheep were sacrificed. Hemodynamics was assessed by catheters in the pulmonary artery and the aorta, and extravascular lung water index (EVLWI) was determined with the single transpulmonary thermodilution technique. Gas exchange was evaluated at baseline and at cessation of the experiment. Data were analyzed by analysis of variance; a P value of less than 0.05 was regarded as statistically significant.
Results: OA induced profound hypoxemia, increased right atrial and pulmonary artery pressures and EVLWI markedly, and decreased cardiac index. rhAPC counteracted the OA-induced changes in EVLWI and arterial oxygenation and reduced the OA-induced increments in right atrial and pulmonary artery pressures.
Conclusions: In ovine OA-induced lung injury, rhAPC dampens the increase in pulmonary artery pressure and counteracts the development of lung edema and the derangement of arterial oxygenation.URI: http://hdl.handle.net/10037/2149 File(s) in this item: 1
article.pdf (486.2Kb) -
Zanaboni, Paolo; Wootton, Richard (Journal article; Tidsskriftartikkel; Peer reviewed, 2012)[+][-]
Abstract: Today there is much debate about why telemedicine has stalled. Teleradiology is the only widespread telemedicine application. Other telemedicine applications appear to be promising candidates for widespread use, but they remain in the early adoption stage. The objective of this debate paper is to achieve a better understanding of the adoption of telemedicine, to assist those trying to move applications from pilot stage to routine delivery. URI: http://hdl.handle.net/10037/4427 File(s) in this item: 1
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Øiesvold, Terje; Nivison, Mary; Hansen, Vidje; Skre, Ingunn; Østensen, Line; Sørgaard, Knut (Journal article; Tidsskriftartikkel; Peer reviewed, 2013)[+][-]
Abstract: Background This study will explore the validity of psychiatric diagnoses in administrative registers with special emphasis on comorbid anxiety and substance use disorders. Methods All new patients admitted to psychiatric hospital in northern Norway during one year were asked to participate. Of 477 patients found eligible, 272 gave their informed consent. 250 patients (52%) with hospital diagnoses comprised the study sample. Expert diagnoses were given on the basis of a structured diagnostic interview (M.I.N.I.PLUS) together with retrospective checking of the records. The hospital diagnoses were blind to the expert. The agreement between the expert’s and the clinicians’ diagnoses was estimated using Cohen’s kappa statistics. Results The expert gave a mean of 3.4 diagnoses per patient, the clinicians gave 1.4. The agreement ranged from poor to good (schizophrenia). For anxiety disorders (F40-41) the agreement is poor (kappa = 0.12). While the expert gave an anxiety disorder diagnosis to 122 patients, the clinicians only gave it to 17. The agreement is fair concerning substance use disorders (F10-19) (kappa = 0.27). Only two out of 76 patients with concurrent anxiety and substance use disorders were identified by the clinicians. Conclusions The validity of administrative registers in psychiatry seems dubious for research purposes and even for administrative and clinical purposes. The diagnostic process in the clinic should be more structured and treatment guidelines should include comorbidity. URI: http://hdl.handle.net/10037/5038 File(s) in this item: 1
article.pdf (148.8Kb) -
Øiesvold, Terje; Bakkejord, Tony Thørring; Hansen, Vidje; Nivison, Mary; Sørgaard, Knut (Journal article; Tidsskriftartikkel; Peer reviewed, 2012)[+][-]
Abstract: The epidemiology of suicidality shows considerable variation across sites. However, one of the strongest predictors of suicide is a suicidal attempt. Knowledge of the epidemiology of suicidal ideas and attempts in the general population as well as in the health care system is of importance for designing preventive strategies. In this study, we will explore the role of the psychiatric hospital in suicide prevention by investigating treated incidence of suicidal ideation and attempt, and further, discern whether sociodemographic, clinical and service utilization factors differ between these two groups at admission. The study was a prospective cohort study on treated incidence in a 1-year period and 12-month follow-up. The two psychiatric hospitals in northern Norway, serving a population of about 500,000 people, participated in the study. A total of 676 first-time admissions were retrospectively checked for suicidality at the time of admission. A study sample of 168 patients was found eligible for logistic regression analysis to elucidate the risk profiles of suicidal ideators versus suicidal attempters. GAF, HoNOS and SCL-90-R were used to assess symptomatology at baseline. 52.2% of all patients admitted had suicidal ideas at admission and 19.7% had attempted suicide. In the study sample, there were no differences in risk profile between the two groups with regard to sociodemographic and clinical factors. Males who had made a suicide attempt were less likely to have been in contact with an out-patient clinic before the attempt. The rating scales not measuring suicidality directly showed no differences in symptomatology. The findings provide evidence for the importance of the psychiatric hospital in suicide prevention. About half of the admissions were related to suicidality and the similar risk profiles found in suicidal ideators and suicidal attempters indicate that it is the ideators who mostly need treatment that get admitted to the hospital, and should be evaluated and treated with equal concern as those who have attempted suicide. URI: http://hdl.handle.net/10037/4973 File(s) in this item: 1
article.pdf (200.2Kb) -
Øiesvold, Terje; Nivison, Mary; Hansen, Vidje; Sørgaard, Knut; Østensen, Line; Skre, Ingunn (Journal article; Tidsskriftartikkel; Peer reviewed, 2012)[+][-]
Abstract: Background This study has explored the classification of bipolar disorder in psychiatric hospital. A review of the literature reveals that there is a need for studies using stringent methodological approaches. Methods 480 first-time admitted patients to psychiatric hospital were found eligible and 271 of these gave written informed consent. The study sample was comprised of 250 patients (52%) with hospital diagnoses. For the study, expert diagnoses were given on the basis of a structured diagnostic interview (M.I.N.I.PLUS) and retrospective review of patient records. Results Agreement between the expert's and the clinicians' diagnoses was estimated using Cohen's kappa statistics. 76% of the primary diagnoses given by the expert were in the affective spectrum. Agreement concerning these disorders was moderate (kappa ranging from 0.41 to 0.47). Of 58 patients with bipolar disorder, only 17 received this diagnosis in the clinic. Almost all patients with a current manic episode were classified as currently manic by the clinicians. Forty percent diagnosed as bipolar by the expert, received a diagnosis of unipolar depression by the clinician. Fifteen patients (26%) were not given a diagnosis of affective disorder at all. Conclusions Our results indicate a considerable misclassification of bipolar disorder in psychiatric hospital, mainly in patients currently depressed. The importance of correctly diagnosing bipolar disorder should be emphasized both for clinical, administrative and research purposes. The findings questions the validity of psychiatric case registers. There are potential benefits in structuring the diagnostic process better in the clinic. URI: http://hdl.handle.net/10037/4436 File(s) in this item: 1
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Øie, Cristina Ionica; Appa, Rupa Shree; Hilden, Ida; Petersen, Helle Heibroch; Gruhler, Albrecht; Smedsrød, Bård; Hansen, John-Bjarne (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: The low density lipoprotein receptor-related protein-1 (LRP-1) is a large, multifunctional endocytic receptor from the LDL receptor family, highly expressed in liver parenchymal cells (PCs), neurons, activated astrocytes, and fibroblasts. The aim of the study was to investigate if liver sinusoidal endothelial cells (LSECs), highly specialized scavenger cells, express LRP-1. To address this question, experiments were performed in vivo and in vitro to determine if receptor associated protein (RAP) and trypsin-activated α2-macroglobulin (α2M∗) were endocytosed in LSECs. Both ligands were cleared from the circulation mainly by the liver. Hepatocellular distribution of intravenously administered ligands, assessed after magnetic bead cell separation using LSEC- and KC-specific antibodies, showed that PCs contained 93% and 82% of liver-associated 125I-RAP and 125I-α2M∗, whereas 5% and 11% were associated with LSECs. Uptake of RAP and α2M∗ in the different liver cell population in vitro was specific and followed by degradation. The uptake of 125I-RAP was not inhibited by ligands to known endocytosis receptors in LSECs, while uptake of 125I-α2M∗ was significantly inhibited by RAP, suggesting the involvement of LRP-1. Immunofluorescence using LRP-1 antibody showed positive staining in LSECs. Ligand blot analyses using total cell proteins and 125I-RAP followed by mass spectrometry further confirmed and identified LRP-1 in LSECs. LSECs express functional LRP-1. An important implication of our findings is that LSECs contribute to the rapid removal of blood borne ligands for LRP-1 and may thus play a role in lipid homeostasis. Description: This paper is part of Cristina Ionica Øie's doctoral thesis, which is available in Munin at http://hdl.handle.net/10037/2910 URI: http://hdl.handle.net/10037/4078 File(s) in this item: 1
article.pdf (2.615Mb) -
Øie, Cristina Ionica; Appa, Rupa Shree; Hilden, Ida; Brodin, Ellen; Smedsrød, Bård; Hansen, John-Bjarne (Preprint; Manuskript; Peer reviewed, 2010)[+][-]
Abstract: Background: Tissue factor pathway inhibitor (TFPI) plays an important role for the anticoagulant effect of heparin. Depletion of intravascular TFPI by treatment with unfractionated heparin (UFH), and not by low molecular weight heparin (LMWH), has been suggested to explain the superiority of LMWH in treatment of both arterial and venous thrombosis. The present study was undertaken to investigate the impact of UFH on clearance kinetics, and organs and cells responsible for the clearance of recombinant human full length TFPI purified from baby hamster kidney cells (TFPIBHK) and from E.Coli (TFPIE.Coli).
Methods: Male Sprague-Dawley rats were used as research animals. TFPIBHK and TFPIE.Coli were labelled with 125I, and used to study clearance in vivo.
Results: Surface Plasmon Resonance (SPR) analysis revealed that both types of TFPI bound to UFH in vitro, but TFPIE.Coli exhibited a faster association rate and a much slow dissociation rate. Intravenous administration of 100 IU/kg UFH immediately prior to TFPI decreased the circulatory survival (t1/2α) of TFPIBHK from 1.99 ± 0.10 min to 1.17 ± 0.13 min (p<0.001) without affecting the fast clearance of TFPIE.Coli. Presence of UFH significantly increased the circulatory survival during the slow t1/2β phase of TFPIE.Coli from 27.44 ± 1.91 min to 36.88 ± 1.87 min (p<0.05) without affecting the t1/2β of TFPIBHK. Hepatocellular distribution of radiolabeled ligands showed that both forms of TFPI were mainly taken up by PCs in the absence of UFH (≥ 90%). UFH administration switched the hepatocellular distribution of TFPIE.Coli from PCs towards LSECs, without affecting the distribution of TFPIBHK.
Conclusions: Our findings revealed a specific increase in the elimination of TFPIBHK during UFH treatment. This observation may represent the underlying mechanism for depletion of endogenous TFPI in humans during UFH treatment.Description: This paper is part of Cristina Ionica Øie's doctoral thesis, which is available in Munin at http://hdl.handle.net/10037/2910 URI: http://hdl.handle.net/10037/2913 File(s) in this item: 1
article.pdf (247.6Kb) -
Øie, Cristina Ionica; Appa, Rupa Shree; Brodin, Ellen; Hansen, John-Bjarne; Smedsrød, Bård (Preprint; Manuskript; Peer reviewed, 2010)[+][-]
Abstract: We here report on a study carried out to determine the early clearance kinetics, and organ, cell(s) and receptor(s) responsible for the clearance of full length TFPI purified from BHK cells (TFPIBHK). Following intravenous administration, 125I-TFPIBHK was cleared with a biphasic elimination curve, and with a significantly slower t1/2α compared to recombinant human TFPI from E.Coli (TFPIE.Coli) (1.95±0.10 versus 1.42±0.07 min, respectively, p<0.001). Studies on organ and cell distribution revealed that liver parenchymal cells (PCs) were responsible for 96% of the uptake of TFPIBHK and 81% of TFPIE.Coli, whereas the nonparenchymal cells (NPCs) were responsible for 4% and 19%, respectively. Pre-administration of excessive amounts of unlabeled TFPIBHK prolonged blood clearance of 125I-TFPIBHK. Unlabelled TFPIBHK inhibited endocytosis of 125I-TFPIBHK in PCs in vitro, whereas blocking of LDL-receptor related protein-1 (LRP-1) by receptor-associated protein (RAP) affected neither blood clearance nor endocytosis of 125I-TFPIBHK in PCs. In addition, TFPIBHK was also found in the kidneys and this could be reduced in the presence of RAP. Asialoorosomucoid (ASOR), a potent inhibitor of the asialoglycoprotein receptor (ASGP-R), prolonged the circulatory survival of 125I-m-TFPI by 1.5-fold (p<0.001). In vitro, ASOR and other ASGP-R antagonists significantly inhibited endocytosis of 125I-TFPIBHK in PCs. Moreover, unlabelled TFPIBHK markedly decreased endocytosis of 125I-asialofetuin. In conclusion, our findings suggest that ASGP-R mediated endocytosis in the liver is involved in the clearance of TFPIBHK. Description: This article is part of Cristina Ionica Øie's doctoral thesis, which is available in Munin at http://hdl.handle.net/10037/2910 URI: http://hdl.handle.net/10037/2912 File(s) in this item: 1
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