| 1. |
- Baun, Michael, et al.
(författare)
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Pharmacological characterization and expression of VIP and PACAP receptors in isolated cranial arteries of the rat
- 2011
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 670:1, s. 186-194
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Tidskriftsartikel (refereegranskat)abstract
- Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) are potent vasodilators in animals and humans. PACAP infusion but not VIP infusion precipitates migraine attacks in migraine patients. The vascular effects of VIP and the two varieties of PACAP (PACAP-27 and PACAP-38) were investigated versus selective antagonists in segments of rat middle cerebral arteries (MCA), basilar arteries (BA) and middle meningeal arteries (MMA) using myographs. The luminal and abluminal effects of VIP were studied using perfusion myograph. mRNA expression of the relevant receptors (VPAC(1), VPAC(2) and PAC(1)) was examined by in situ hybridization. There was no significant difference in relaxant potency of the peptides in the MCA. In BA the relaxant potency was VIP>PACAP-27 = PACAP-38. Relaxant responses were either absent or very weak in MMA. VIP was found to be somewhat more potent in BA than in the MCA. Maxadilan, a selective PAC(1)-receptor agonist, showed no relaxant effect in either vessel. The VPAC(2)-antagonist PG 99-465 alone proved ineffective in the MCA, while it had a weak effect on BA. The VPAC(1)-antagonist PG 97269 inhibited relaxation induced by both VIP and the PACAPs in cerebral vessels. In combination, the two antagonists demonstrated better effect than either alone. VIP applied luminally via perfusion myograph caused no dilatation, indicating lack of endothelial involvement. In situ hybridization demonstrated the presence of mRNA for all three receptors in the smooth muscle cells of the vessels. In conclusion, migraine-like headache induced by PACAP-38 infusion is unlikely to be caused by direct vasodilator action on intracranial vessels. (C) 2011 Elsevier B.V. All rights reserved.
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| 2. |
- Juhl, Louise, et al.
(författare)
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Effect of two novel CGRP-binding compounds in a closed cranial window rat model
- 2007
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 567:1-2, s. 117-124
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the in vivo effects of two novel calcitonin gene-related peptide (CGRP) binding molecules in the genuine closed cranial window model in the rat. The RNA-Spiegelmer (NOX-C89) and the monoclonal CGRP antibody are CGRP scavengers and might be used as an alternative to CGRP-receptor antagonists in the treatment of migraine. Rats were anaesthetized and a closed cranial window established. Changes in dural and pial artery diameter and mean arterial blood pressure were measured simultaneously. Infusion of the RNA-Spiegelmer or the CGRP antibody alone had no effect on the arteries or the mean arterial blood pressure. We then used a bolus of 0.3 mu g/kg CGRP (n=6) or electrical stimulation (25 V, 5 Hz, 1 ms pulse width and of 10 s of duration) (n=6) to induce dilatation of dural and pial arteries (mediated via CGRP-receptors). Pre-treatment with the RNA-Spiegelmer inhibited CGRP-induced vasodilatation of the dural artery (from 38 +/- 17% to 7 +/- 3%) and the pial artery (from 14 +/- 1% to 3 +/- 2%) (P < 0.05). The RNA-Spiegelmer, however, did not significantly inhibit dilatation induced by electrical stimulation (P > 0.05). The CGRP antibody caused a significant reduction of the dural artery diameter caused by intravenous CGRP-in fusion (from 23 +/- 5% to 12 +/- 3%) (P < 0.05), but did not inhibit dilatation caused by electrical stimulation (P > 0.05). In conclusion, the CGRP scavengers effectively inhibited the effect of circulating CGRP but do not modify the effect of electdcal stimulation and the consequent liberation of CGRP from perivascular sensory nerve fibres. (c) 2007 Elsevier B.V. All rights reserved.
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| 3. |
- Ploug, Kenneth Beri, et al.
(författare)
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Pharmacological and molecular comparison of K-ATP channels in rat basilar and middle cerebral arteries
- 2006
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 553:1-3, s. 254-262
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Tidskriftsartikel (refereegranskat)abstract
- ATP-sensitive potassium (K-ATP) channels play an important role in the regulation of cerebral vascular tone. In vitro studies using synthetic K-ATP channel openers suggest that the pharmacological profiles differ between rat basilar arteries and rat middle cerebral arteries. To address this issue, we studied the possible involvement of endothelial K-ATP channels by pressurized arteriography after luminal administration of synthetic K-ATP channel openers to rat basilar and middle cerebral arteries. Furthermore, we examined the mRNA and protein expression profile of K-ATP channels to rat basilar and middle cerebral arteries using quantitative real-time PCR (Polymerase Chain Reaction) and Western blotting, respectively. In the per-fusion system, we found no significant responses after luminal application of three K-ATP channel openers to rat basilar and middle cerebral arteries. In contrast, abluminal application caused a concentration-dependent dilatation of both arteries, that was more potent in basilar than in middle cerebral arteries. Quantitative real-time PCR detected the presence of mRNA transcripts of the K-ATP channel subunits Kir6.1, Kir6.2, SUR1 and SLTR2B, while SUR2A mRNA was barely detected in both rat basilar and middle cerebral arteries. Of the five mRNAs, the expression levels of Kir6.1 and SUR2B transcripts were predominant in both rat basilar and middle cerebral arteries. Western blotting detected the presence of Kir6.1, Kir6.2, SUR1 and SUR2B proteins in both arteries. Densitometric measurements of the Western blot signals further showed higher expression levels of Kir6.1 and SUR2B proteins in rat middle cerebral arteries than was found in rat basilar arteries. In conclusion, our in vitro pharmacological studies showed no evidence for functional endothelial K-ATP channels in either artery. Furthermore, the results indicate that Kir6.1/SUR2B is the major K-ATP channel complex in rat basilar and middle cerebral arteries.
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| 4. |
- Gustavsson, Anders, et al.
(författare)
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Corrigendum to “Cost of disorders of the brain in Europe 2010” [Eur. Neuropsychopharmacol. 21 (2011) 718–779]
- 2012
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 22:3, s. 237-238
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Tidskriftsartikel (refereegranskat)abstract
- The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people.
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| 5. |
- Gustavsson, Anders, et al.
(författare)
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Cost of disorders of the brain in Europe 2010.
- 2011
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Ingår i: European Neuropsychopharmacology. - Amsterdam : Elsevier BV. - 0924-977X .- 1873-7862. ; 21:10, s. 718-79
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people.AIMS: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country.METHODS: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27+Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010.RESULTS: The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US.DISCUSSION: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges.RECOMMENDATIONS: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.
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| 6. |
- Wienberg, Jes, et al.
(författare)
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Fortresses, Storehouses and Symbols - ambiguous churches of the Baltic Sea
- 2004
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Ingår i: Der Ostseeraum und Kontinentaleuropa 1100-1600 : Einflussnahme - Rezeption - Wandel - Einflussnahme - Rezeption - Wandel. - 393574935X ; 8, s. 35-50
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Fortresses, Storehouses and Symbols - ambiguous churches of the Baltic Sea: Källa on Öland is used as a point of departure in a discussion of the so-called defensive churches or multi-functional churches at the Baltic Sea. The categorization of medieval society into four separate spheres, the church, the castle, the town and the countryside, is criticised as having created a heterogenous group of deviant churches. The deviant churches have been interpreted in three competitive perspectives: 1) defense, 2) profane function and 3) symbolic form. However, to understand the deviant churches it is necessary to combine the perspectives. The multi-functional churches represented a fusion, where the sacred and the profane were integrated. The whole point was, that a broad specter of functions such as hostelry, residence and store were made sacred by being integrated in the church building or church yard. Most of the multi-functional churches at the Baltic Sea belong to the period c. 1170-1240 and might be connected to the Danish empire, the crusades and the Saint Canute Guilds. When peace broke down in the 1240s, some of the multi-functional churches were symbolically fortified as also several towns and many manors.
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