| 1. |
- Hjelm, F, et al.
(author)
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Antibody-mediated regulation of the immune response
- 2006
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In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 64:3, s. 177-184
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Journal article (peer-reviewed)abstract
- Antibodies administered in vivo together with the antigen they are specific for can regulate the immune response to that antigen. This phenomenon is called antibody-mediated feedback regulation and has been known for over 100 years. Both passively administered and actively produced antibodies exert immunoregulatory functions. Feedback regulation can be either positive or negative, resulting in >1000-fold enhancement or >99% suppression of the specific antibody response. Usually, the response to the entire antigen is up- or downregulated, regardless of which epitope the regulating antibody recognizes. IgG of all isotypes can suppress responses to large particulate antigens like erythrocytes, a phenomenon used clinically in Rhesus prophylaxis. IgG suppression works in mice lacking the known Fc-gamma receptors (FcgammaR) and a likely mechanism of action is epitope masking. IgG1, IgG2a and IgG2b administered together with soluble protein antigens will enhance antibody and CD4+ T-cell responses via activating FcgammaR, probably via increased antigen presentation by dendritic cells. IgG3 as well as IgM also enhance antibody responses but their effects are dependent on their ability to activate complement. A possible mechanism is increased B-cell activation caused by immune complexes co-crosslinking the B-cell receptor with the complement-receptor 2/CD19 receptor complex, known to lower the threshold for B-cell activation. IgE-antibodies enhance antibody and CD4+ T-cell responses to small soluble proteins. This effect is entirely dependent on the low-affinity receptor for IgE, CD23, the mechanism probably being increased antigen presentation by CD23+ B cells.
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| 2. |
- Hjelm, F, et al.
(author)
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IgG3-mediated enhancement of the antibody response is normal in Fc gammaRI-deficient mice
- 2005
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In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 62:5, s. 453-461
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Journal article (peer-reviewed)abstract
- Antibodies, administered together with their specific antigen, can feedback-regulate antibody responses to this antigen. IgG1, IgG2a and IgG2b enhance antibody responses to soluble protein antigens. This effect is primarily mediated by FcRs as enhancement is impaired in FcR gamma-/- mice, reported to lack Fc gammaRI and Fc gammaRIII because of deletion of the common FcR gamma chain. Also IgG3 can enhance antibody responses. However, this effect is unperturbed in FcR gamma-/- mice but severely impaired in complement-depleted animals and in animals lacking complement receptor 1 and 2. Although this argues against involvement of Fc gammaRs, FcR gamma-/- mice may express one-fifth of the normal levels of Fc gammaRI and, in addition, Fc gammaRI has been suggested to bind IgG3. We re-investigated the dependence of IgG3-mediated enhancement on Fc gammaRs using a mouse strain selectively lacking Fc gammaRI and found that IgG3-mediated enhancement is completely normal. Unlike IgE and IgG2a, which are both thought to enhance T-cell proliferation via FcR-mediated antigen presentation, IgG3 was a poor enhancer of T-cell proliferation both in vivo and in vitro. These findings argue against a significant involvement of Fc gammaRs in IgG3-mediated enhancement of antibody responses and support our previous conclusion that complement plays a major role.
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| 3. |
- Kalla, R., et al.
(author)
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Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease
- 2021
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In: Journal of Crohn's & Colitis. - : Elsevier. - 1873-9946 .- 1876-4479. ; 15:5, s. 699-708
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Journal article (peer-reviewed)abstract
- BACKGROUND: Success in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD).METHODS: We conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins.RESULTS: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including MMP-12 (Holm adjusted p=4.1×10 -23 ) and OSM (p=3.7×10 -16). Nine of these proteins associate with cis- germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including IL-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively.CONCLUSION: We have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings.
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| 4. |
- Bergemalm, Daniel, 1977-, et al.
(author)
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Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
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In: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
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Journal article (peer-reviewed)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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| 5. |
- Forss, Anders, et al.
(author)
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Prospective observational study on Stelara (ustekinumab) assessing effectiveness in Crohn's disease (PROSE) : a 16-week follow-up
- 2021
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In: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 56:6, s. 680-686
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Journal article (peer-reviewed)abstract
- BACKGROUND: Prospectively and systematically collected real-world data on the effectiveness of ustekinumab (anti-interleukin-12/23) for treating Crohn's disease (CD) are still limited.AIM: To assess the short-term real-world effectiveness of ustekinumab in Swedish patients with active CD.METHODS: Prospective multicentre study of adult CD patients initiating ustekinumab according to recommended doses at 20 hospitals, between January 2017 and November 2018. Data were collected through an electronic case report form (eCRF) linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG). The primary outcomes were clinical response (≥3-point-decrease of Harvey-Bradshaw index (HBI)) and remission (HBI ≤4 points) at week 16. Secondary outcomes included C-reactive protein (CRP) and haemoglobin (Hb) at baseline compared to week 16.RESULTS: Of 114 included patients, 107 (94%) had failed >= 1 and 58 (51%) >= 2 biological agents (anti-tumour necrosis factor [aTNF] agents or vedolizumab). The 16-week ustekinumab retention rate was 105 (92%). Data on HBI at baseline were available for 96 patients. At week 16, response or remission was achieved in 38/96 (40%) patients (25/96 (26%) achieving clinical remission and 23/96 (24%) showing a clinical response). The median CRP concentration (N = 65) decreased from 6 to 4 mg/l (p = .006). No significant changes in Hb were observed. No incident malignancies or infections, requiring antibiotic treatment, were reported. CONCLUSIONS: In this nation-wide prospective real-world study of adult patients with CD, ustekinumab was associated with clinical effectiveness when administered according to clinical practice and seemed to represent a safe treatment option.
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| 6. |
- Forss, Anders, et al.
(author)
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Ustekinumab Is Associated with Real-World Long-Term Effectiveness and Improved Health-Related Quality of Life in Crohn's Disease
- 2023
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In: Digestive Diseases and Sciences. - : Kluwer Academic Publishers. - 0163-2116 .- 1573-2568. ; 68:1, s. 65-76
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Journal article (peer-reviewed)abstract
- BACKGROUND: Prospectively and systematically collected long-term real-world clinical data on ustekinumab (anti-interleukin-12/23) are still scarce.AIMS: To assess the long-term effectiveness of ustekinumab in patients with active Crohn's disease (CD).METHODS: This is a prospective multicenter study of adult patients with CD initiating ustekinumab according to recommended doses at 20 Swedish hospitals. The primary outcome was clinical remission (Harvey-Bradshaw Index (HBI) ≤ 4 points) at weeks 52 and 104. Secondary outcomes included clinical response (≥ 3-point-decrease in HBI among patients with initial HBI ≥ 5 points), treatment retention, and biomarkers (C-reactive protein (CRP), hemoglobin, fecal-calprotectin) at weeks 52 and 104 compared to baseline. We also reported Health-related Quality of Life (HRQoL) measures.RESULTS: Of 114 included patients, 107 (94%) had previously failed ≥ 1 and 58 (51%) ≥ 2 anti-tumor necrosis factor agents. Forty (35%) had failed anti-integrin agents. Ustekinumab retention rates at weeks 52 and 104 were 70% (n = 80/114) and 61% (n = 69/114), respectively. Clinical response was seen in 36% (n = 25/69) and 29% (n = 20/69) of the patients, and remission was achieved in 32% (n = 31/96) and 29% (n = 28/96) at weeks 52 and 104, respectively. Median HBI and CRP levels decreased significantly at both timepoints as compared to baseline. Significant improvements were also observed in HRQoL. Adverse events were reported in 11% (n = 13/114) of the patients, including five cases of severe adverse events. No malignancies were observed.CONCLUSIONS: In this nationwide prospective real-world 104-week-follow-up study of adult patients with active CD, ustekinumab was associated with long-term clinical effectiveness and improvement in HRQoL measures when used in routine clinical care.
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| 7. |
- Gustafsson (f.d. Emilsson), Sara, et al.
(author)
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Strategiskt och verkningsfullt? : Ledningsverktygs bidrag till kommuners hållbarhetsarbete
- 2011
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Reports (other academic/artistic)abstract
- Kommuner kan pekas ut som nyckelaktörer i arbetet för en mer hållbar utveckling. De verkar nära medborgarna och utgör en länk mellan medborgare och nationella/internationella myndigheter och aktörer. Vi har haft förmånen att under en tioårsperiod följa svenska kommuners arbete med att organisera och systematisera arbetet för ett mer hållbart lokalsamhälle. Under den tiden har vi sett en trend som innebär att det har blivit allt vanligare att kommuner tar på sig ansvar utöver det lagstadgade och arbetar mer proaktivt för ett hållbart lokalsamhälle. Det finns en uppsjö av verktyg som kommuner (och andra organisationer) kan använda för att få stöd i detta arbete. Många är förenklade och anpassade varianter av ISO 14001 och EMAS, som är internationellt accepterade verktyg, för att strukturera och systematisera miljöarbetet i en organisation. Den här rapporten är en syntes av de studier som vi har genomfört under det senaste decenniet. Det empiriska underlaget baseras främst på intervjuer (allt från fokusgruppintervjuer till telefonintervjuer), dokumentstudier och observationer. Rapporten syftar till att diskutera om och hur ledningsverktyg kan bidra till ett mer effektivt och verkningsfullt strategiskt miljö- och hållbarhetsarbete i kommuner. Centralt för syntesen har varit att reflektera över de verktyg som kommunerna väljer att använda, på vilket sätt verktygen används samt hur detta arbete integreras i den kommunala organisationen. Vår forskning tar sin utgångspunkt i miljöperspektivet i hållbar utveckling i och med att vi initialt studerade hur kommuner arbetar med att införa standardiserade miljöledningssystem. Vi har följt många kommuner från deras första, ofta trevande, försök till att införa miljöledningssystem till att de har ledningssystem som integrerar miljöperspektivet med de övriga perspektiven i hållbar utveckling. Denna utveckling beskriver vi i de tre utvecklingsfaserna: interna miljöledningssystem, mogna miljöledningssystem samt hållbarhetsledningssystem. Utvecklingen har gått från en ganska snäv systemsyn, både vad gäller innehåll och aktörer i systemen, till en vidare systemsyn där olika perspektiv och flera aktörer involveras. Ett internt miljöledningssystem kännetecknas bland annat av att det främst är miljöexperterna i organisationen som är involverade, att miljöledningen sker särkopplat från verksamhetsstyrningen och att kommunerna ofta väljer att begränsa detta arbete till de tekniska förvaltningarna. I ett moget miljöledningssystem har miljöledningsarbetet en mer central roll i organisationen där de flesta verksamheter och de flesta anställda är involverade. Ett moget miljöledningssystem innebär också att kommunen har en större kunskap om vilket angreppssätt som passar de lokala förutsättningarna. Det resulterar ofta i lokalt utarbetade modeller för hur miljöledningssystemsarbetet ska organiseras och implementeras. Många kommuner inser efter en tid att det är svårt att hantera miljöfrågan i ett separat system som är skiljt från den övriga styrningen och flera upplever att de andra perspektiven i hållbar utveckling borde kunna hanteras med samma systematik som miljöfrågorna. Därför har det blivit allt vanligare att kommuners miljöledningssystem utvecklats till hållbarhetsledningssystem. Dessa har liknande egenskaper som ett moget miljöledningssystem vad gäller intern spridning och position, men det omfattar alla tre perspektiven i hållbar utveckling och bygger på en bredare samverkan där även externa intressenter är inkluderade. En av rapportens viktigaste slutsatser är att det är svårt för kommuner att styra i riktning mot en mer hållbar utveckling. En anledning till det är begreppet ”hållbar utvecklings” komplexitet. Det är ett begrepp som har visat sig ha olika innebörd för olika aktörer. Verksamhetsstyrning utgår från att man har tydliga mål och om man vill styra för en mer hållbar utveckling är det viktigt att ha en viss samsyn kring vad det är man vill uppnå. Ett sätt att underlätta införandet av ett miljö- och hållbarhetsledningssystem är att utgå från de strukturer och ansvarsposter som redan existerar i organisationen samt att utforma ett arbetssätt som är anpassat till dem som ska använda det. Annars riskerar ledningssystemet att bli en hyllvärmare, som inte får något genomslag i det praktiska arbetet, och som därmed begränsas i verkningsfullhet. Vi tror att ledningsverktyg kan bidra med struktur och inspiration för kommuners arbete med att organisera och systematisera sitt miljö- och hållbarhetsarbete, men det är viktigt att kommunerna reflekterar över varför de gör den här typen av insats samt om dessa gör nytta i förhållande till kommunens huvudprocesser.
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| 8. |
- Hendriks, Jeroen, et al.
(author)
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Cardiac disease and stroke : Practical implications for personalised care in cardiac-stroke patients. A state of the art review supported by the Association of Cardiovascular Nursing and Allied Professions
- 2020
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In: European Journal of Cardiovascular Nursing. - : Oxford University Press (OUP). - 1474-5151 .- 1873-1953. ; 19:6, s. 495-504
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Research review (peer-reviewed)abstract
- Cardiac and stroke conditions often coexist because of common risk factors. The occurrence of stroke may have significant consequences for patients with cardiac conditions and their caregivers and poses a major burden on their lives. Although both cardiac and stroke conditions are highly prevalent, primary stroke prevention in cardiac patients is crucial to avert disabling limitations or even mortality. In addition, specific interventions may be needed in the rehabilitation and follow-up of these patients. However, healthcare systems are often fragmented and are not integrated enough to provide specifically structured and individualised management for the cardiac-stroke patient. Cardiac rehabilitation or secondary prevention services are crucial from this perspective, although referral and attendance rates are often suboptimal. This state of the art review outlines the significance of primary stroke prevention in cardiac patients, highlights specific challenges that cardiac-stroke patients and their caregivers may experience, examines the availability of and need for structured, personalised care, and describes potential implications for consideration in daily practice.
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| 9. |
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| 10. |
- Hjelm, Mats, et al.
(author)
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Monte Carlo study of high-field carrier transport in 4H-SiC including band-to-band tunneling
- 2003
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In: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 93:2, s. 1099-1107
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Journal article (peer-reviewed)abstract
- A full-band ensemble Monte Carlo simulation has been used to study the high-field carrier transport properties of 4H-SiC. The complicated band structure of 4H-SiC requires the consideration of band-to-band tunneling at high electric fields. We have used two models for the band-to-band tunneling; one is based on the overlap test and the other on the solution of the multiband Schrodinger equations. The latter simulations have only been performed for holes in the c-axis direction, since the computer capacity requirement are exceedingly high. Impact-ionization transition rates and phonon scattering rates have been calculated numerically directly from the full band structure. Coupling constants for the phonon interaction have been deduced by fitting of the simulated low-field mobility as a function of lattice temperature to experimental data. Secondary hot electrons generated as a consequence of hole-initiated impact ionization are considered in the study for both models of band-to-band tunneling. When the multiband Schrodinger equation model is used for holes in the c-axis direction, a significant change in the electron energy distribution is found, since the hole impact-ionization rate is very much increased with this model. The secondary electrons increase the average energy of the electron distribution leading to a significant increase in the electron-initiated impact-ionization coefficients. Our simulation results clearly show that both electrons and holes have to be considered in order to understand electron-initiated impact ionization in 4H-SiC
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