| 1. |
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| 2. |
- Ederle, Joerg, et al.
(författare)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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Ingår i: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Tidskriftsartikel (refereegranskat)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 3. |
- Uhlin, F., et al.
(författare)
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Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study
- 2022
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Ingår i: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 33:4, s. 829-838
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Tidskriftsartikel (refereegranskat)abstract
- Background The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treat-ment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis.& nbsp;Methods An investigator-driven phase 2a one-arm study (EudraCT 2016-004082-39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR < 15 ml/min per 1.73m(2). All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months.& nbsp;Results At inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m(2). The median age was 61 years (range 19-77), six were women, and six were also positive for anti-neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (P < 0.001, Fisher's exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug.& nbsp;Conclusions In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial.
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| 5. |
- Hjorth, Stephan, 1953, et al.
(författare)
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(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752)-a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent
- 2020
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 374:3, s. 404-419
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe for the first time the distinctive pharmacological profile for (35)-3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 mu mol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypo-activity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to similar to 250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to similar to 250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptannine 7 receptor and alpha 2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on cate-cholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT This report describes the distinctive preclinical profile of (3S)3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.
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| 6. |
- Sonesson, C, et al.
(författare)
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Regiochemical control and suppression of double bond isomerization in the Heck arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole
- 1996
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Ingår i: Journal of Organic Chemistry. - UNIV UPPSALA, UPPSALA BIOMED CTR, DEPT ORGAN PHARMACEUT CHEM, S-75123 UPPSALA, SWEDEN. : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 61:14, s. 4756-4763
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Forskningsöversikt (refereegranskat)abstract
- Arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole under standard Heck reaction conditions produces a mixture of compounds. The olefin undergoes two types of palladium-catalyzed reactions: (a) arylation to provide C-3 arylated derivatives and (b) competing double bond isomerization. Addition of silver carbonate and thallium acetate fully suppressed the isomerization, and good yields of C-3 substituted compounds were achieved after arylation with aryl halides. With regard to aryl triflates as arylating agents, addition of lithium chloride was necessary to promote the Heck reaction. This additive excluded the use of silver and thallium salts, but high regioselectivity and good yields could be obtained by employing tri-2-furylphosphine as ligand. Arylation was rendered both regioselective and enantioselective (58% ee) with 1-naphthyl triflate as substrate utilizing a (R)-BINAP/thallium acetate combination. The C-3 arylated enamides were converted further into the corresponding 3-arylpyrrolidines.
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| 7. |
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| 8. |
- Björn, Lars Olof, et al.
(författare)
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Effects of ozone depletion and increased ultraviolet-B radiation on northern vegetation
- 1999
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Ingår i: Polar Research. - : Norwegian Polar Institute. - 0800-0395 .- 1751-8369. ; 18:2, s. 331-337
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Tidskriftsartikel (refereegranskat)abstract
- The stratospheric ozone layer has been depleted at high and mid-latitudes as a consequence of man's pollution of the atmosphere, and this results in increasing ultraviolet-B radiation at ground level. We investigate the effects of further radiation increases on plants and ecosystems by irradiating natural sub-Arctic and Arctic vegetation with artificial W-B radiation in field experiments extending over several years. Our experimental sites are located at Abisko, in northern Sweden (68 degrees N), and Adventdalen, on the island of Spitsbergen (78 degrees N). Additional UV-B induced interspecific differences in plant response in terms of reduced (or, in one case, increased) growth, changed morphology and changed pigment content. In some cases effects seem to be accumulated from one year to another. Plant litter decomposition is retarded. We are also studying how UV-B enhancement may affect the interaction between species. In some experiments we combine UV-B enhancement with changes in other factors: carbon dioxide concentration, water availability, and temperature. In some cases the effect of radiation enhancement is modified, or even reversed, by such changes. Over a four year period we did not find any significant radiation induced change in species composition, but based on the effects on individual plant species, such changes can be expected to take place over a longer time.
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| 9. |
- Björn, Lars Olof, et al.
(författare)
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The problem of ozone depletion in northern Europe
- 1998
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Ingår i: Ambio: a Journal of Human Environment. - 0044-7447. ; 27:4, s. 275-279
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Tidskriftsartikel (refereegranskat)abstract
- Ozone in the atmosphere, mainly in the stratosphere, absorbs most of the ultraviolet-B (wavelength 280-315 nm) radiation from the sun, which can destroy DNA and other biologically important molecules and, thereby, damage living organisms. Due to the pollution of the atmosphere by humans, the ozone layer is presently being depleted, more rapidly at higher latitudes than at lower, and more rapidly over Scandinavia than over most geographical regions at corresponding latitudes. Ultraviolet-B radiation is generally more intense in mountain regions than at sea level. We have experiments in progress in which we simulate the effects of further ozone depletion on terrestrial ecosystems (mountain heaths, bogs, tundra) by irradiating them with artificial ultraviolet-B radiation. Effects on the growth of dwarf-shrubs and mosses and on plant litter decomposition are described.
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| 10. |
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| 11. |
- Davies, Roy C, et al.
(författare)
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A Practical Example Using VR in the Assessment of Brain Injury
- 1998
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Ingår i: The International Journal of Virtual Reality. - 1081-1451. ; 3:4, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Virtual Reality (VR) as a complementary tool for medical practitioners in the assessment and rehabilitation of people who have suffered a traumatic brain injury (TBI) is discussed. A pilot-study has been undertaken on a prototype VR assessment tool. The design involved nine occupational therapists with expertise in the care of traumatic brain injured patients and one (computer experienced) patient. The aim was to begin a dialogue and to ascertain the potential of a VR system. A common method for occupational therapists to assess function and ability is to ask a patient to brew coffee. From the performance of such a task, an individual’s “functional signature” can be determined. The prototype was built using Superscape, a personal computer based VR system, to be close to the real coffee making task, including effects of making mistakes, realistic graphics and sound effects. The world was designed to be as easy to use and intuitive as possible, though problems of mental abstraction level, transfer of training and realistic interaction have yet to be resolved. The comments from the test participants have highlighted problem areas, given positive insight and pointed out other scenarios where VR may be of use in the rehabilitation of people with a traumatic brain injury.
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| 17. |
- Graf, Wilhelm, et al.
(författare)
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Results after sacral nerve stimulation for chronic constipation
- 2015
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 27:5, s. 734-739
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sacral nerve stimulation is an established treatment for fecal incontinence and initial reports describe successful results also in subjects with chronic constipation.METHODS: Consecutive patients with slow transit or outlet obstruction type constipation were offered external stimulation through a test electrode inserted in a sacral foramen during a 3-week period. The symptomatic evaluation was based on the number of bowel movements and a validated obstructed defecation score (ODS). A permanent implant was performed provided an overall 50% decrease in symptoms was observed.KEY RESULTS: In total, 44 patients with chronic constipation were treated with a 3-week test stimulation. Fifteen experienced a 50% reduction of symptoms and received a permanent implant. Four of the 15 with permanent implants were explanted during the course of the study. Five subjects (11% of original group) reported sustained symptom relief at final follow-up after a mean of 24 months (range 4-81). Mean ODS score did not change during the treatment. Patients with predominantly slow transit constipation or outlet obstruction did not differ concerning success rate.CONCLUSIONS & INFERENCES: Sacral nerve stimulation has limited efficacy in unselected patients with chronic constipation and cannot be recommended for treatment on routine basis.
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| 18. |
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| 19. |
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| 20. |
- Johanson, U, et al.
(författare)
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The effects of an enhanced UV-B radiation on a sub-arctic heath ecosystem
- 1995
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Ingår i: Ambio: a Journal of Human Environment. - 0044-7447. ; 24:2, s. 106-112
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the effects of increased UV-B radiation on a natural subarctic ecosystem a field irradiation experiment was established at Abisko, northern Sweden. The vegetation in the plots consists of a dwarf shrub layer with mosses and lichens beneath. Many response variables of the vegetation and soil are measured in these plots, e.g. photosynthesis, growth, phenology, changes in species composition and decomposition. This paper describes the methods used and some initial results. Decomposition was imparied by enhanced UV-B radiation. UV-B directly affected decomposition processes and also affected them indirectly by altering the tissue chemistry of leaves. The annual growth of the dwarf shrubs was lower under enhanced UV-B. This was more pronounced in evergreen than in deciduous species. Leaf thickness of the dwarf shrubs was changed by UV-B. The leaves of the evergreen Vaccinium vitis-idaea grew thicker, while those of the two deciduous species V. myrtillus and V. uliginosum grew thinner. In the moss Hylocomium splendens, the phenological development was accelerated under enhanced UV-B radiation. Its growth (number of primary branches, length and dry weight) also increased.
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| 21. |
- Jordan, Stanley C., et al.
(författare)
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Imlifidase desensitization in crossmatch-positive, highly-sensitized kidney transplant recipients : Results of an international phase 2 trial (Highdes)
- 2021
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 105:8, s. 1808-1817
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Highly-HLA sensitized patients have limited access to life-saving kidney transplantation due to a paucity of immunologically suitable donors. Imlifidase is a cysteine protease that cleaves IgG leading to a rapid decrease in antibody level and inhibition of IgG-mediated injury. This study investigates the efficacy and safety of imlifidase in converting a positive crossmatch test to negative, allowing highly sensitized patients to be transplanted with a living or deceased donor kidney.METHODS: This open-label, single arm, phase 2 trial conducted at five transplant centers, evaluated the ability of imlifidase to create a negative crossmatch test within 24 hours. Secondary endpoints included post-imlifidase DSA levels compared to pre-dose levels, renal function, and pharmacokinetic/pharmacodynamic profiles. Safety endpoints included adverse events and immunogenicity profile.RESULTS: 89.5% of the transplanted patients demonstrated conversion of baseline positive crossmatch to negative within 24 hours after imlifidase treatment. DSA most often rebounded 3-14 days post-imlifidase dose, with substantial interpatient variability. Patient survival was 100% with graft survival of 88.9% at 6 months. 38.9% had early biopsy proven antibody mediated rejection with onset 2-19 days post-transplantation. Serum IgG levels began to normalize after ~3-7 days post-transplantation. Anti-drug antibody levels were consistent with previous studies. Seven adverse events in six patients were classified as possibly or probably related to treatment and were mild-moderate in severity.CONCLUSIONS: Imlifidase was well tolerated, converted positive crossmatches to negative, and enabled patients with a median cPRA of 99.83% to undergo kidney transplantation resulting in good kidney function and graft survival at 6 months.
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| 22. |
- Kvist, Joanna, et al.
(författare)
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Translation and measurement properties of the Swedish version of ACL-Return to Sports after Injury questionnaire
- 2013
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley-Blackwell. - 0905-7188 .- 1600-0838. ; 23:5, s. 568-575
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Tidskriftsartikel (refereegranskat)abstract
- Psychological factors may be a hindrance for returning to sport after an anterior cruciate ligament (ACL) reconstruction. The ACL-Return to Sport after Injury scale (ACL-RSI) measures athletes emotions, confidence in performance, and risk appraisal in relation to return to sport. The aim of this study was to translate the ACL-RSI scale from English to Swedish and to examine some of the measurement properties of the Swedish version. The ACL-RSI was translated and culturally adapted. A professional expert group and five patients evaluated face validity. One hundred and eighty-two patients completed the translated ACL-RSI, a project-specific questionnaire, the Tampa Scale of Kinesiophobia (TSK), the Knee-Self-Efficacy Scale (K-SES), the Multidimensional Health Locus of Control (MHLC-C), the Knee injury and Osteoarthritis Outcome Score (KOOS), and the Anterior Cruciate Ligament-Quality of Life (ACL-QoL) questionnaires. Fifty-three patients answered the ACL-RSI twice to examine reproducibility. The ACL-RSI showed good face validity, internal consistency (Cronbachs alpha=0.948), low floor and ceiling effects and high construct validity when evaluated against the TSK, K-SES, MHLC-C, KOOS, and ACL-QoL scales. The reproducibility was also high (intra-class correlation=0.893). Therefore, the ACL-RSI can be used to evaluate psychological factors relevant to returning to sport after ACL reconstruction surgery.
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| 23. |
- Lindén, Anita, et al.
(författare)
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Special Considerations for Navigation and Interaction in Virtual Environments for People with Brain Injury
- 2000
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Ingår i: Proceedings of the 3rd International Conference on Disability, Virtual Reality & Associated Technologies. ; , s. 287-296
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Konferensbidrag (refereegranskat)abstract
- When a Virtual Environment (VE) is designed, decisions regarding the navigation of the viewpoint, interaction with objects, and the behavior of the VE itself are made. Each of these can affect the usability and the cognitive load on the user. A VE that had previously been constructed as a prototype tool for the assessment of brain injury has been studied to establish the consequences of such design decisions. Six people, two with brain injury, have used the VE to perform a specific task (brewing coffee) a total of ten times over two sessions separated by a week. These trials were video recorded and analysed. Results and implications are presented and discussed.
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| 24. |
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| 25. |
- Nilsson, Marie, 1968, et al.
(författare)
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The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition
- 2004
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Ingår i: Prog Neuropsychopharmacol Biol Psychiatry. - : Elsevier BV. - 0278-5846. ; 28:4, s. 677-85
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Tidskriftsartikel (refereegranskat)abstract
- The Carlsson research group has developed a series of compounds capable of stabilising the dopamine system without inducing the deleterious hypodopaminergia that encumbers the currently used antipsychotic drugs. In the present study one of these dopaminergic stabilisers, ACR16, was tested in a mouse model for cognitive deficits of schizophrenia and autism. Since we believe that hypoglutamatergia is a key element in both schizophrenia and autism we used mice rendered hypoglutamatergic by treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. MK-801 causes both hyperactivity and a behavioural primitivization. ACR16 attenuated the MK-801-induced hyperactivity and, in addition, caused a marked improvement of behavioural quality with a movement pattern approaching that of control animals. Since we believe that the impoverishment of the behavioural repertoire caused by MK-801 may correspond to the cognitive deficits seen in schizophrenia and autism, these results suggest that ACR16 may improve cognitive status in these disorders.
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| 26. |
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| 30. |
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| 31. |
- Robinson, N. A., et al.
(författare)
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Applying genetic technologies to combat infectious diseases in aquaculture
- 2022
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Ingår i: Reviews in Aquaculture. - : Wiley. - 1753-5123 .- 1753-5131. ; 15:2, s. 491-535
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Tidskriftsartikel (refereegranskat)abstract
- Disease and parasitism cause major welfare, environmental and economic concerns for global aquaculture. In this review, we examine the status and potential of technologies that exploit genetic variation in host resistance to tackle this problem. We argue that there is an urgent need to improve understanding of the genetic mechanisms involved, leading to the development of tools that can be applied to boost host resistance and reduce the disease burden. We draw on two pressing global disease problems as case studies—sea lice infestations in salmonids and white spot syndrome in shrimp. We review how the latest genetic technologies can be capitalised upon to determine the mechanisms underlying inter- and intra-species variation in pathogen/parasite resistance, and how the derived knowledge could be applied to boost disease resistance using selective breeding, gene editing and/or with targeted feed treatments and vaccines. Gene editing brings novel opportunities, but also implementation and dissemination challenges, and necessitates new protocols to integrate the technology into aquaculture breeding programmes. There is also an ongoing need to minimise risks of disease agents evolving to overcome genetic improvements to host resistance, and insights from epidemiological and evolutionary models of pathogen infestation in wild and cultured host populations are explored. Ethical issues around the different approaches for achieving genetic resistance are discussed. Application of genetic technologies and approaches has potential to improve fundamental knowledge of mechanisms affecting genetic resistance and provide effective pathways for implementation that could lead to more resistant aquaculture stocks, transforming global aquaculture. © 2022 The Authors. Reviews in Aquaculture published by John Wiley & Sons Australia, Ltd.
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| 32. |
- Romner, Bertil, et al.
(författare)
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Late magnetic resonance imaging related to neurobehavioral functioning after aneurysmal subarachnoid hemorrhage
- 1989
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Ingår i: Neurosurgery. - 0148-396X. ; 25:3, s. 390-396
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Tidskriftsartikel (refereegranskat)abstract
- Twenty patients who underwent early aneurysm surgery--that is, surgery within 72 hours after rupture--underwent further follow-up examination including magnetic resonance imaging (MRI) of the brain and a comprehensive neuropsychological assessment. Significant statistical correlation between tissue loss as seen on a late MRI scan and neurobehavioral deficits could not be established. Among 9 patients with no tissue loss seen on MRI, 3 exhibited substantial cognitive dysfunction and 6 had mild impairment. Three patients showed minor but corresponding tissue loss and deficits. In 3 patients with pronounced pathological indications on MRI, evidence of cognitive dysfunction was absent in 2, and 1 patient showed substantial impairment. The remaining 5 individuals displayed moderate pathological indications on MRI, with no obvious correspondence to cognitive functioning. In 7 patients, small white matter lesions, probably silent infarcts not seen on computed tomographic scan, were discovered on MRI. There was a clear relationship between arterial hypertension prior to aneurysm rupture and the extent of tissue loss seen on MRI. Absence of pathological findings on MRI scan did not exclude cognitive malfunctioning, and vice-versa.
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| 33. |
- Sonesson, Björn C, et al.
(författare)
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UVB-induced inflammation gives increased d-dopachrome tautomerase activity in blister fluid which correlates with macrophage migration inhibitory factor.
- 2003
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Ingår i: Experimental Dermatology. - : Wiley. - 0906-6705. ; 12:3, s. 278-282
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Tidskriftsartikel (refereegranskat)abstract
- UVB light was used to induce an experimental inflammation in normal human skin in order to investigate its correlation with the activity of the newly described enzyme d-dopachrome tautomerase (DDT) in the fluid of experimental blisters. Macrophage migration inhibitory factor (MIF) activity was determined as a closely related marker of inflammation. DDT and MIF activities were demonstrated in blister fluids in all 10 healthy subjects. All but one of these subjects showed increased activity of DDT and MIF after three minimal erythemal doses (MED) of UVB. The mean activity of DDT increased approximately twofold and the mean activity of MIF also increased twofold after UVB in our experimental model. We found a strong correlation between DDT and MIF activities. The presence of DDT in epidermis and its increase at UV irradiation was confirmed by immunohistochemical studies. In this study, DDT is for the first time demonstrated in the skin. It is also the first time DDT can be related to inflammation, and its covariation with MIF strengthens this observation.
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| 34. |
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| 35. |
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| 36. |
- Soveri, Inga, et al.
(författare)
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The IgG-degrading enzyme of Streptococcus pyogenes causes rapid clearance of anti-glomerular basement membrane antibodies in patients with refractory anti-glomerular basement membrane disease
- 2019
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 96:5, s. 1234-1238
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Tidskriftsartikel (refereegranskat)abstract
- In anti-glomerular basement membrane (anti-GBM) disease, IgG class autoantibodies induce rapidly progressive glomerulonephritis. Regrettably, many patients are diagnosed at a late stage when even intensive conventional treatment fails to restore renal function The endopeptidase IdeS (Immunoglobulin G degrading enzyme of Streptococcus pyogenes) (imliflidase) rapidly cleaves all human IgG subclasses into F(ab')(2) and Fc fragments. We received permission to treat three patients with refractory anti-GBM nephritis without pulmonary involvement on a compassionate basis. All patients were dialysis-dependent for days or weeks when treated, and all had high levels of circulating anti-GBM despite plasma exchange. A single dose of IdeS led to complete clearance of circulating anti-GBM antibodies in all three patients. After about a week, all rebounded but the rebounds were easily managed by plasma exchange in two of three cases. Renal histology demonstrated severe crescentic glomerulonephritis with acute but mainly chronic changes. Staining for the Fc fragment was negative in all while Fab was positive in two patients. Unfortunately, none of the patients regained independent renal function. Thus, treatment with IdeS led to rapid clearance of circulating and kidney bound antiGBM antibodies. The clinical utility, dosing and usage to preserve renal function remain to be determined.
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| 37. |
- Svenningsson, P., et al.
(författare)
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A Phase 2a Trial Investigating the Safety and Tolerability of the Novel Cortical Enhancer IRL752 in Parkinson's Disease Dementia
- 2020
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 35:6, s. 1046-1054
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Tidskriftsartikel (refereegranskat)abstract
- Background IRL752 is a novel small-molecule compound that acts to regioselectively enhance norepinephrine, dopamine, and acetylcholine neurotransmission in the cerebral cortex. Objective The primary objective of the trial was to investigate the safety and tolerability of IRL752 in patients with Parkinson's disease and dementia. Methods Patients with Parkinson's disease and dementia were randomized to IRL752 or placebo treatment (3:1 ratio) for 28 days. The study drug was given as an adjunct treatment to the patients' regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days after which the dose was kept stable for an additional 14 days. Results A total of 32 patients were randomized to treatment, and 29 patients completed the 4-week treatment. Adverse events were generally mild and transient and were mostly reported during the dose titration phase. There were 2 serious adverse events, and none of them were related to the experimental treatment. The average dose achieved in the stable dose phase was 600 mg daily, yielding a 2-hour postdose plasma concentration of about 4 mu M on day 28. Exploratory assessment of secondary outcomes indicated efficacy for symptoms and signs known to be poorly responsive to levodopa. Conclusions IRL752 appears to be safe and well tolerated for a 4-week treatment in patients with Parkinson's disease and dementia. (c) 2020 International Parkinson and Movement Disorder Society
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| 38. |
- Svenningsson, P, et al.
(författare)
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Safety and tolerability of IRL790 in Parkinson’s disease with levodopa-induced dyskinesia—a phase 1b trial
- 2018
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Ingår i: NPJ Parkinson's Disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- IRL790 is a novel compound with psychomotor stabilizing properties primarily targeting the dopamine D3 receptor. IRL790 is developed as an experimental treatment for levodopa-induced dyskinesia (LID), impulse control disorder, and psychosis in Parkinson’s disease (PD). The primary objective was to investigate the safety and tolerability of IRL790 in PD patients with LID in a randomized controlled trial. PD patients with peak-dose dyskinesia were randomized to placebo or IRL790 treatment (1:3 ratio) for 4 weeks. Study drug was given as an adjunct treatment to the patients’ regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days, whereafter dosing was kept stable for an additional 14 days. Fifteen patients were randomized to treatment and 13 patients completed the 4-week treatment. Adverse events were mostly reported during the titration phase of the trial. They were mainly central nervous system related and could be mitigated by dose adjustments. There were no serious adverse events. There were no clinically significant changes in vital signs, electrocardiogram, and laboratory parameters due to the treatment. The average dose in the stable dose phase was 18 mg daily, yielding a 2-h post-dose plasma concentration of average 229 nM on day 28. Assessments for motor function showed a numeric reduction in dyskinesia. It is concluded that IRL790 can be safely administered to patients with advanced PD. The results will be of guidance for the design of phase 2 studies.
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- van der Riet, Claire, et al.
(författare)
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Supra-and Infra-Renal Aortic Neck Diameter Increase after Endovascular Repair of a Ruptured Abdominal Aortic Aneurysm
- 2022
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Hypovolemia-induced hypotension may lead to an aortic diameter decrease in patients with a ruptured abdominal aortic aneurysm (rAAA). This study investigates the changes in supra-and infra-renal aortic neck diameters before and after endovascular aortic aneurysm repair (EVAR) for rAAA and the possible association with endograft apposition. A retrospective cohort study was conducted including 74 patients treated between 2010 and 2019 in two large European vascular centers. Outer-to-outer wall diameters were measured at +40, +10, 0, −10, and −20 mm relative to the lowest renal artery baseline on the last pre-and first post-EVAR computed tomography angiography (CTA) scan in a vascular workstation. Endograft apposition was determined on the first post-EVAR CTA scan. The post-operative diameter was significantly (p < 0.001) larger than the preoperative diameter at all aortic levels. The aortic diameter at +40 mm (supra-renal) and −10 mm (infra-renal) increased by 6.2 ± 7.3% and 12.6 ± 9.8%, respectively. The aortic diameter at +40 mm increased significantly more in patients with low preoperative systolic blood pressure (<90 mmHg; p = 0.005). A shorter apposition length was associated with a higher aortic diameter increase (R = −0.255; p = 0.032). Hypovolemic-induced hypotension results in a significant decrease in the aortic diameter in patients with an rAAA, which should be taken into account when oversizing the endograft.
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- Waters, Susanna, et al.
(författare)
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In Vivo Systems Response Profiling and Multivariate Classification of CNS Active Compounds: A Structured Tool for CNS Drug Discovery
- 2017
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Ingår i: Acs Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 8:4, s. 785-797
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the application of in vivo systems response profiling in CNS drug discovery by a process referred to as the Integrative Screening Process. The biological response profile, treated as an array, is used as major outcome for selection of candidate drugs. Dose response data, including ex vivo brain monoaminergic biomarkers and behavioral descriptors, are systematically collected and analyzed by principal component analysis (PCA) and partial least-squares (PLS) regression, yielding multivariate characterization across compounds. The approach is exemplified by assessing a new class of CNS active compounds, the dopidines, compared to other monoamine modulating compounds including antipsychotics, antidepressants, and procognitive agents. Dopidines display a distinct phenotypic profile which has prompted extensive further preclinical and clinical investigations. In summary, in vivo profiles of CNS compounds are mapped, based on dose response studies in the rat. Applying a systematic and standardized work-flow, a database of in vivo systems response profiles is compiled, enabling comparisons and classification. This creates a framework for translational mapping, a crucial component in CNS drug discovery.
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- Waters, Susanna, et al.
(författare)
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Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease
- 2018
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Ingår i: Journal of Huntingtons Disease. - : IOS Press. - 1879-6397 .- 1879-6400. ; 7:1, s. 1-16
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Forskningsöversikt (refereegranskat)abstract
- Despite advances in understanding the pathophysiology of Huntington's disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect. This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.
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