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- Grännö, O., et al.
(författare)
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Preclinical protein signatures in blood predict Crohn's disease and Ulcerative colitis several years before the diagnosis
- 2024
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 18:Suppl. 1, s. I660-I661
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: We aimed to identify protein signatures predictive of a future diagnosis of inflammatory bowel disease (IBD).Methods: We conducted a case-control study, nested within large population-based cohorts with biorepositories. Samples were obtained from individuals who later in life were diagnosed with IBD (preclinical cases) and compared with age and sex-matched individuals who remained free from IBD during follow-up (controls). Using proximity extension assays (Olink, Uppsala), we measured 176 proteins. We applied regularized logistic regression to identify protein signatures of preclinical disease in serum from the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222). The biological relevance of identified proteins was further assessed in an inception cohort (n=144). Finally, we used an IBD twin cohort (n=327) to examine the impact of genetic and shared environmental factors on identified proteins.Results: We identified 34 proteins associated with preclinical Crohn’s disease (CD) in the discovery cohort (Pfalse discovery rate <0.10), with 9 confirmed in the validation cohort (Pfalse discovery rate <0.05). For preclinical ulcerative colitis (UC), 45 proteins were identified and 12 validated (Fig. 1A-B). In the discovery cohort, a signature of 29 proteins differentiated preclinical CD cases from controls with an AUC of 0.85 (Fig. 1G). Its performance was confirmed when applied to the preclinical validation cohort (AUC=0.84, Fig. 1H). Moreover, the signature had excellent capacity to differentiate newly diagnosed CD from healthy controls in the inception cohort (AUC = 0.99, Fig. 1I). The preclinical UC signature had a significant, but albeit lower, predictive capacity in the discovery (AUC=0.77), validation (AUC=0.67) and inception cohort (AUC=0.90, Fig. 1G-I).15 of 17 proteins associated with preclinical IBD demonstrated significantly higher intra-pair correlation coefficients in healthy monozygotic- compared to dizygotic twin pairs, indicating an influence from genetic factors on the regulation of these protein markers. The preclinical signature for CD demonstrated an AUC of 0.87 when comparing twins with preclinical CD (n=10) to matched external healthy twins. However, its predictive capacity was lower when comparing preclinical CD twins with their healthy twin siblings (AUC=0.58), i.e., when accounting for genetic and shared environmental factors. The difference in AUC estimates in the twin cohort was not significant (P=0.07).
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| 8. |
- Kochar, Bharati, et al.
(författare)
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Prevalence and Implications of Frailty in Older Adults With Incident Inflammatory Bowel Diseases : A Nationwide Cohort Study
- 2022
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 20:10, s. 2358-2365
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: We aimed to compare the risk of frailty in older adults with incident inflammatory bowel disease (IBD) and matched non-IBD comparators and assess the association between frailty and future hospitalizations and mortality.Methods: In a cohort of patients with incident IBD ≥60 years of age from 2007 to 2016 in Sweden identified using nationwide registers, we defined frailty using Hospital Frailty Risk Score. We compared prevalence of frailty in patients with IBD with age, sex, place of residency– and calendar year–matched population comparators. In the IBD cohort, we used Cox proportional hazards modeling to examine the associations between frailty risk and hospitalizations or mortality.Results: We identified 10,590 patients with IBD, 52% female with a mean age of 71 years of age, matched to 103,398 population-based comparators. Among patients with IBD, 39% had no risk for frailty, 49% had low risk for frailty, and 12% had higher risk for frailty. Mean Hospital Frailty Risk Score was 1.9 in IBD and 0.9 in matched comparators (P < .01). Older adults with IBD at higher risk for frailty had a 20% greater risk for mortality at 3 years compared with those who were not frail. Compared with nonfrail older patients with IBD, patients at higher risk for frailty had increased mortality (hazard ratio [HR], 3.22, 95% confidence interval [CI], 2.86–3.61), all-cause hospitalization (HR, 2.42; 95% CI, 2.24–2.61), and IBD-related hospitalization (HR, 1.50; 95% CI, 1.35–1.66). These associations were not attenuated after adjusting for comorbidities.Conclusions: Frailty is more prevalent in older adults with IBD than in matched comparators. Among older patients with IBD, frailty is associated with increased risk for hospitalizations and mortality.
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- Nyberg, L., et al.
(författare)
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Observational study of tofacitinib in ulcerative colitis in Sweden (ODEN) - Interim analysis of clinical and biomarker data
- 2024
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 18:Suppl. 1, s. I1703-I1704
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Tofacitinib is a Janus kinase (JAK) inhibitor for the treatment of moderate to severe ulcerative colitis (UC). ODEN is an ongoing Swedish multicentre prospective observational study regarding effectiveness of tofacitinib in UC. In this interim analysis, we aimed to assess the clinical outcomes during the first 16 weeks.Methods: Patients with active UC were enrolled 2020-2023 when starting tofacitinib as per clinical indication. Inclusion criteria were fecal (F) calprotectin >250 mg/kg or Mayo endoscopic score ≥2. Data were collected using an electronic case report form linked to the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG). Data concerning inflammatory markers, endoscopic activity, partial (p) Mayo, extra intestinal manifestations, health-related quality of life measures, corticosteroid use, and colectomy rates were collected regardless of tofacitinib discontinuation. Information collected at week 8 and 16 is presented here. Intention-to-treat (ITT) analysis was applied and tofacitinib discontinuation was considered as treatment failure (i.e., no tofacitinib-induced clinical or laboratory response or remission). McNemar’s test was used for proportion differences.Results: The proportion of patients who previously had failed at least one biologic was 95% and at least two biologics, 62%. At inclusion, median p-Mayo was 5 and 39% of patients were on corticosteroids (Table 1a). Patients’ survival on drug is shown in Figure 1a. At week 8 and 16, 42% and 43%, respectively, achieved corticosteroid free clinical remission, Figure 1b. A 50% reduction in F-calprotectin was seen in 54% and 49% at week 8 and 16, respectively. The endpoint of Mayo endoscopic score 0 and/or F-calprotectin <100 mg/kg was achieved by 30% and 38% at week 8 and 16, respectively. Arthralgia frequency decreased significantly from baseline from 29% at inclusion to 13% and 11% at week 8 and 16 respectively. Three patients underwent colectomy the first 16 weeks (Table 1b).Conclusion: After 16 weeks of treatment with tofacitinib, a substantial proportion of previously treatment refractory UC patients were in clinical and endoscopic corticosteroid-free remission, and a distinct improvement in F-calprotectin levels was observed. In addition, a significant reduction in arthralgia was noted.
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- Nyberg, L., et al.
(författare)
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Observational study of tofacitinib in Ulcerative Colitis in Sweden (ODEN) - Interim analysis of health-related quality of life and fatigue
- 2024
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 18:Suppl. 1, s. I1887-I1889
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Ulcerative colitis (UC) has a major impact on daily life. The Janus Kinas (JAK) inhibitor tofacitinib is effective in achieving remission in UC, but prospective real-world evidence concerning the effect on health-related quality of life (HRQoL) and fatigue are still scarce. Fatigue is a component of UC that is notoriously difficult to treat and not unambiguously related to inflammatory activity. ODEN is an ongoing Swedish multicentre prospective observational study of tofacitinib in UC. In this interim analysis, we assessed the effectiveness on HRQoL and fatigue during the first 16 weeks.Methods: Patients with UC and active inflammation were enrolled 2020-2023 when starting tofacitinib as per clinical indication. To measure various aspects of impairment of daily life, the validated questionnaires Short Health Scale (SHS), EQ-5D-5L [Swedish value set], and IBD-fatigue scale (IBD-F) were used. These data and information concerning clinical, biochemical, and endoscopic outcomes were collected in an e-CRF linked to the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG). For HRQoL outcomes, per protocol analysis was applied. Paired t-test and Wilcoxon’s signed-rank test were used for mean and median differences, respectively.Results: In total, 103 patients were included. Baseline data are shown in Table 1a. For patients still on tofacitinib treatment, all four dimensions of the SHS (symptoms, social function, disease related worry, and general well-being) improved significantly, Table 1b. A median decrease of one point from baseline was seen at week 8 in each of the parameters, which was maintained through week 16 with a tendency towards further improvement. EQ-5D-5L showed an impairment mainly in the aspects of pain/discomfort and ability to participate in common daily activities. Improvement in these dimensions was seen from baseline to week 16. The overall EQ-5D-5L index improved significantly from baseline (0.80) to week 8 (0.86) and week 16 (0.89), as did the EQ VAS 0-100 reflecting overall health (58, 71, and 74, respectively). A significant improvement in IBD-F part 1 and 2 was seen at week 8 and 16, Figure 1.Conclusion: This study demonstrates that tofacitinib treatment covariates with positive changes in a variety of measures of patients’ quality of life, including improvements in self-assessed overall wellbeing. Finally, fatigue significantly improved during tofacitinib treatment. Thus, tofacitinib treatment shows association with meaningful improvements in multiple aspects of quality of life during the first 16 weeks of treatment.
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| 15. |
- Shrestha, Sarita, 1991-, et al.
(författare)
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The use of ICD codes to identify IBD subtypes and phenotypes of the Montreal classification in the Swedish National Patient Register
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 55:4, s. 430-435
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Whether data on International Classification of Diseases (ICD)-codes from the Swedish National Patient Register (NPR) correctly correspond to subtypes of inflammatory bowel disease (IBD) and phenotypes of the Montreal classification scheme among patients with prevalent disease is unknown. Materials and methods: We obtained information on IBD subtypes and phenotypes from the medical records of 1403 patients with known IBD who underwent biological treatment at ten Swedish hospitals and retrieved information on their IBD-associated diagnostic codes from the NPR. We used previously described algorithms to define IBD subtypes and phenotypes. Finally, we compared these register-generated subtypes and phenotypes with the corresponding information from the medical records and calculated positive predictive values (PPV) with 95% confidence intervals. Results: Among patients with clinically confirmed disease and diagnostic listings of IBD in the NPR (N = 1401), the PPV was 97 (96-99)% for Crohn's disease, 98 (97-100)% for ulcerative colitis, and 8 (4-11)% for IBD-unclassified. The overall accuracy for age at diagnosis was 95% (when defined as A1, A2, or A3). Examining the validity of codes representing disease phenotype, the PPV was 36 (32-40)% for colonic Crohn's disease (L2), 61 (56-65)% for non-stricturing/non-penetrating Crohn's disease behaviour (B1) and 83 (78-87)% for perianal disease. Correspondingly, the PPV was 80 (71-89)% for proctitis (E1)/left-sided colitis (E2) in ulcerative colitis. Conclusions: Among people with known IBD, the NPR is a reliable source of data to classify most subtypes of prevalent IBD, even though misclassification commonly occurred in Crohn's disease location and behaviour and also among IBD-unclassified patients.
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| 16. |
- Visuri, Isabella, 1991-, et al.
(författare)
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Anti-TNF agent drug survival in patients with IBD : real-world comparisons of individual anti-TNF agents based on the Swedish National Quality Registry for IBD (SWIBREG)
- 2019
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Ingår i: Journal of Crohn's & Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 13, s. S443-S444
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Studies comparing drug survival in different anti-tumour necrosis factor (TNF) agents in IBD patients are scarce, especially for second-line anti-TNF agents. We aimed to (A) assess drug survival and predictors of response and adverse drug reactions to first-line anti-TNF treatment and (B) examine drug survival for individual anti-TNF agents when used as second-line anti-TNF. Methods: Well-characterised patients with IBD (n = 955) starting their first anti-TNF treatment between 2006 and 2016 (Table 1), were identified from the Swedish National Quality Registry for IBD (SWIBREG). Drug survival was examined, stratified by reason for discontinuation, that is, lack/loss of clinical effectiveness or adverse drug reactions. Multi-variable Cox regression models were used to identify predictors of drug survival. Drug survival for the second anti-TNF was assessed by type of first anti-TNF agent. Results: Risk factors at baseline for shorter drug survival, in patients with Crohn’s disease, were use of infliximab as first-line anti-TNF (compared with adalimumab, adjusted HR = 1.95, 95% CI: 1.19‒3.18) (Figure 1A) and colonic disease (L2) (compared with ileal disease (L1) and ileocolonic disease (L3), adjusted HR = 2.16, 95% CI: 1.25‒3.74). Consistently, Crohn’s disease patients who switched from adalimumab to infliximab had shorter drug survival, compared with those who switched from infliximab to adalimumab (Figure 1B). A normalisation of CRP level at 3 months was associated with decreased risk of short drug survival in both Crohn’s disease (adjusted HR = 0.40, 95% CI: 0.19‒0.81) and ulcerative colitis (adjusted HR = 0.40, 95% CI: 0.19‒0.86). In Crohn’s disease, but not in ulcerative colitis, immunomodulators were associated with a lower risk of short drug survival due to adverse drug reactions (adjusted HR = 0.50, 95% CI: 0.31‒0.82). Conclusions: Drug survival duration was longer for adalimumab compared with infliximab both when used as first anti-TNF agent and when used as second-line treatment. The consistent pattern indicates that these differences are not only explained by channelling bias (differential prescribing behaviour).
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- Angelison, Leif, et al.
(författare)
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Long-term outcome of infliximab treatment in chronic active ulcerative colitis : a Swedish multicentre study of 250 patients
- 2017
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley-Blackwell Publishing Inc.. - 0269-2813 .- 1365-2036. ; 45:4, s. 519-532
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Tidskriftsartikel (refereegranskat)abstract
- Background: Real-life long-term data on infliximab treatment in ulcerative colitis are limited.Aim: To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined.Methods: A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age ≥18 years, ambulatory treated, steroid-dependent or intolerant and/or immunomodulator refractory or intolerant.Results: Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10-17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy.Conclusions: Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy.
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| 20. |
- Bain, C. C., et al.
(författare)
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Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6C(hi) monocyte precursors
- 2013
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 6:3, s. 498-510
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Tidskriftsartikel (refereegranskat)abstract
- Macrophages (m phi) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete m phi populations carry out these distinct functions or if resident m phi change during inflammation. We show here that most resident m phi in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCII hi, but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1(int) cells is present in resting colon and it expands during experimental colitis. Ly6C(hi) CCR2(+) monocytes can give rise to all m phi subsets in both healthy and inflamed colon and we show that the CX3CR1int pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1 hi m phi. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory m phi. Phenotypic analysis of human intestinal m phi indicates that analogous processes occur in the normal and Crohn's disease ileum. These studies show for the first time that resident and inflammatory m phi in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.
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- Grip, O., et al.
(författare)
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Inflammatory bowel disease promotes venous thrombosis earlier in life
- 2000
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 35:6, s. 619-623
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with inflammatory bowel disease (IBD) may be at increased risk of having venous thromboembolism. Methods: Medical records from 1253 IBD patients attending hospital care during the years 1987-97 were studied. These patients were recruited from a population of 340,000 inhabitants. Patients with verified venous thrombosis were characterized clinically, and blood samples were examined for coagulopathy including analyses of antithrombin, plasminogen, protein C, protein S, factor V, and prothrombin mutations. As control groups we used 99 patients with verified venous thrombosis and no history of IBD and 288 volunteers with no history of thrombosis. Results: The incidence of venous thrombosis was 1.5/1000 IBD patients per year, which is comparable to the background population. The mean age was significantly lower in IBD patients than in non-IBD patients (53 versus 64 years, P = 0.0225). We found one patient with antithrombin deficiency but none with protein C, protein S, or plasminogen deficiency. Factor V mutation was as prevalent in IBD patients with thrombosis as in thrombotic non-IBD patients (27% versus 28%) and 3.0 times (95% confidence interval, 0.8-11.9) more frequent in IBD patients with thrombosis than in healthy controls. Prothrombin mutation was not detected in IBD patients with venous thrombosis. Conclusion: We found no increased incidence of venous thrombosis in IBD patients compared with a background population. However, IBD patients had venous thrombosis earlier in life than non-IBD patients. Although factor V mutation may contribute to thrombosis, IBD acts as a trigger through mechanisms that still remain unexplained.
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- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 40. |
- Karlsson, Lars O, 1975, et al.
(författare)
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Cyclosporine A, 2.5 mg/kg, Does Not Reduce Myocardial Infarct Size in a Porcine Model of Ischemia and Reperfusion
- 2012
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Ingår i: Journal of cardiovascular pharmacology and therapeutics. - : SAGE Publications. - 1940-4034 .- 1074-2484. ; 17:2, s. 159-63
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In recent years, cyclosporine A (CsA) has emerged as a promising therapy to limit myocardial ischemic-reperfusion injury, presumably by inhibiting the opening of the mitochondrial permeability transition pore. Results from different large animal models are conflicting, however, with failure to prove beneficial effects of 10 mg/kg CsA administered at reperfusion. Recently, a small clinical study using a bolus of 2.5 mg/kg CsA showed promising but not unequivocal results. The aim of the present study was to estimate the magnitude of a possible infarct reduction with the use of the latter regimen in a closed-chest porcine model for ischemia and reperfusion. Materials and METHODS: Pigs underwent catheterization with balloon occlusion of the left descending coronary artery for 40 minutes, followed by reperfusion for 4 hours. They were randomized to receive an intravenous bolus 7 minutes before reperfusion of either 2.5 mg/kg CsA (n = 12) or saline (control, n = 11). Hearts were stained to quantify area at risk and infarct size. RESULTS: Throughout the experiment, there were no differences between the groups in baseline characteristics or hemodynamic variables. CsA treatment did not reduce infarct size as a proportion of area at risk compared with control (51% +/- 6% and 54% +/- 6%, respectively, P = .75). CONCLUSION: In a closed-chest porcine model for myocardial ischemia and reperfusion injury, 2.5 mg/kg CsA administered before reperfusion did not reduce infarct size.
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| 41. |
- Karlsson, Lars O., et al.
(författare)
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Cyclosporine does not reduce myocardial infarct size in a porcine ischemia-reperfusion model.
- 2010
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Ingår i: Journal of Cardiovascular Pharmacology and Therapeutics. - : Sage Publications. - 1074-2484 .- 1940-4034. ; 15:2, s. 182-9
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Tidskriftsartikel (refereegranskat)abstract
- Cyclosporine A (CsA) has been shown to protect against myocardial ischemia and reperfusion (I/R) injury in small animal models. The aim of the current study was to evaluate the effects of CsA on myocardial I/R injury in a porcine model. Pigs were randomized between CsA (10mg/kg; n = 12) or placebo (n = 15) and anesthetized with either isoflurane (phase I) or pentobarbital (phase II). By catheterization, the left descending coronary artery was occluded for 45 minutes, followed by reperfusion for 2 hours. Hearts were stained to quantify area at risk (AAR) and infarct size (IS). Myocardial biopsies were obtained for terminal dUTP nick end labeling and immunoblot analysis of proapoptotic proteins (apoptosis-inducing factor [AIF], BCL2/adenovirus E1B 19-kd interacting protein 3 [BNIP-3], and active caspase-3). Cyclosporine A did not reduce IS/AAR compared with placebo (49% vs 41%, respectively; P = .21). Pigs anesthetized with isoflurane had lower IS/AAR than pigs anesthetized with pentobarbital (39% vs 51%, respectively; P = .03). This reduction in IS/AAR seemed to be attenuated by CsA. Apoptosis-inducing factor protein expression was higher after CsA administration than after placebo (P = .02). Thus, CsA did not protect against I/R injury in this porcine model. The data suggest a possible deleterious interaction of CsA and isoflurane.
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| 42. |
- Karlsson, Lars O, 1975, et al.
(författare)
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Dose-dependent cardioprotection of enkephalin analogue Eribis peptide 94 and cardiac expression of opioid receptors in a porcine model of ischaemia and reperfusion
- 2012
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 674:2-3, s. 378-383
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Tidskriftsartikel (refereegranskat)abstract
- Opioids confer cardioprotection after myocardial ischaemia and reperfusion. The primary aim of the present study was to evaluate the cardioprotective effect of different doses of enkephalin analogue Eribis peptide 94 (EP 94) in a porcine model of ischaemia and reperfusion. A secondary aim was to analyse the impact of ischaemia and reperfusion on the expression of opioid receptor subtypes in the porcine heart. Thirty-four anesthetised pigs underwent 40 min of balloon occlusion of the left anterior descending coronary artery followed by four hours of reperfusion. Pigs were given either vehicle (0.9% NaCl) or one of four doses of EP 94 (0.2, 1, 5 or 25 ug/kg at each administration, respectively), intravenously after 26, 33 and 40 min of ischaemia. Hearts were stained to quantify area at risk and infarct size. mRNA and protein expressions of the opioid receptor subtypes were detected with RT-PCR, immunoblotting and immunohistochemistry in the control and ischaemic/reperfused areas. There was a significant dose-response relationship between higher doses of EP 94 and reduced infarct size. Expression of kappa- and delta-opioid receptors was detected at both mRNA and protein levels. In ischaemic/reperfused areas, an increased expression of mRNA for both receptors was observed, whereas only protein expression for the delta subtype was up-regulated. The mu-opioid receptor was not detected.
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| 43. |
- Karlsson, Lars O, 1975, et al.
(författare)
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Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion
- 2011
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 651:1-3, s. 146-151
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Tidskriftsartikel (refereegranskat)abstract
- Eribis peptide 94 (EP 94) is a novel enkephalin analog, thought to interact with the and delta-opioid receptors. The purpose of the present study was to examine the cardioprotective potential of EP 94 in two clinically relevant porcine models of myocardial ischaemia and reperfusion, and to investigate if such an effect is associated with an increased expression of endothelial nitric oxide synthase (eNOS). Forty-one anesthetized pigs underwent 40 min of coronary occlusion followed by 4 h of reperfusion. In Protocol I, balloon occlusion of the left anterior descending artery was performed with concurrent intravenous administration of (A) vehicle (n = 7), (B) EP 94 (1 ug/kg) after 5, 12, 19 and 26 min of ischaemia (n = 4) or (C) EP 94 (1 ug/kg) after 26, 33, 40 min of ischaemia (n = 6). In Protocol II, open-chest pigs were administered (D) vehicle (n = 6) or (E) 0.2 ug/kg/min of EP 94 (n = 6) through an intracoronary infusion into the jeopardized myocardium, started after 30 min of ischaemia and maintained for 15 min. The hearts were stained and the protein content of eNOS measured. EP 94 reduces infarct size when administered both early and late during ischaemia compared with vehicle (infarct size group A 61.6 +/- 2%, group B 50.2 +/- 3% and group C 49.2 +/- 2%, respectively, P < 0.05), as well as when infused intracoronary (infarct size group D 82.2 +/- 3.9% and group E 61.2 +/- 2.5% respectively, P < 0.01). Phosphorylated eNOS Ser(I177) in relation to total eNOS was significantly increased in the group administered EP 94. indicating activation of nitric oxide production.
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