| 1. |
- Attman, Per-Ola, 1941, et al.
(författare)
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Dyslipidemia of kidney disease.
- 2009
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Ingår i: Current opinion in lipidology. - 1473-6535. ; 20:4, s. 293-9
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: Chronic kidney disease is associated with specific alterations of lipoprotein metabolism that may be linked to accelerated atherosclerosis and cardiovascular disease. This review summarizes current knowledge of the pathophysiology of renal dyslipidemia and the therapeutic options. RECENT FINDINGS: The renal dyslipidemia is characterized by accumulation of intact and partially metabolized triglyceride-rich apoB-containing and apoC-containing lipoproteins. Increased concentrations of atherogenic apoC-III rich lipoproteins, the hallmark of renal dyslipidemia, may result from disturbances of insulin metabolism and action in chronic kidney disease. Novel findings strongly suggest that apoC-III triggers a cascade of pro-inflammatory events, which ultimately can result in endothelial dysfunction and vascular damage. Disappointingly, recently reported intervention trials with statins have failed to show any benefit on cardiovascular disease in patients with advanced renal failure. SUMMARY: During recent years, our understanding of the character and biological significance of the dyslipidemia of chronic kidney disease, and its link to cardiovascular disease, has increased. However, our knowledge about its proper management is still very limited.
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| 2. |
- Gatzinsky, Kliment, et al.
(författare)
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Repetitive transcranial magnetic stimulation of the primary motor cortex in management of chronic neuropathic pain: a systematic review.
- 2021
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Ingår i: Scandinavian journal of pain. - 1877-8879. ; 21:1, s. 8-21
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Forskningsöversikt (refereegranskat)abstract
- Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) with frequencies 5-20 Hz is an expanding non-invasive treatment for chronic neuropathic pain (NP). Outcome data, however, show considerable inhomogeneity with concern to the levels of effect due to the great diversity of treated conditions. The aim of this review was to survey the literature regarding the efficacy and safety of M1 rTMS, and the accuracy to predict a positive response to epidural motor cortex stimulation (MCS) which is supposed to give a more longstanding pain relief.A systematic literature search was conducted up to June 2019 in accordance with the PRISMA guidelines. We used the PICO Model to define two specific clinical questions: (1) Does rTMS of M1 relieve NP better than sham treatment? (2) Can the response to rTMS be used to predict the effect of epidural MCS? After article selection, data extraction, and study quality assessment, the certainty of evidence of treatment effect was defined using the GRADE system.Data on 5-20 Hz (high-frequency) rTMS vs. sham was extracted from 24 blinded randomised controlled trials which were of varying quality, investigated highly heterogeneous pain conditions, and used excessively variable stimulation parameters. The difference in pain relief between active and sham stimulation was statistically significant in 9 of 11 studies using single-session rTMS, and in 9 of 13 studies using multiple sessions. Baseline data could be extracted from 6 single and 12 multiple session trials with a weighted mean pain reduction induced by active rTMS, compared to baseline, of -19% for single sessions, -32% for multiple sessions with follow-up <30 days, and -24% for multiple sessions with follow-up ≥30 days after the last stimulation session. For single sessions the weighted mean difference in pain reduction between active rTMS and sham was 15 percentage points, for multiple sessions the difference was 22 percentage points for follow-ups <30 days, and 15 percentage points for follow-ups ≥30 days. Four studies reported data that could be used to evaluate the accuracy of rTMS to predict response to MCS, showing a specificity of 60-100%, and a positive predictive value of 75-100%. No serious adverse events were reported.rTMS targeting M1 can result in significant reduction of chronic NP which, however, is transient and shows a great heterogeneity between studies; very low certainty of evidence for single sessions and low for multiple sessions. Multiple sessions of rTMS can maintain a more longstanding effect. rTMS seems to be a fairly good predictor of a positive response to epidural MCS and may be used to select patients for implantation of permanent epidural electrodes. More studies are needed to manifest the use of rTMS for this purpose. Pain relief outcomes in a longer perspective, and outcome variables other than pain reduction need to be addressed more consistently in future studies to consolidate the applicability of rTMS in routine clinical practice.
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| 3. |
- Kolsrud, Oscar, et al.
(författare)
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Measured and not estimated glomerular filtration rate should be used to assess renal function in heart transplant recipients.
- 2016
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Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 31:7, s. 1182-9
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Tidskriftsartikel (refereegranskat)abstract
- In organ transplanted patients, impaired renal function is of major prognostic importance and influences therapeutic decisions. Therefore, monitoring of renal function with glomerular filtration rate (GFR) is of importance, both before and after heart transplantation (HTx). The GFR can be measured directly (mGFR) or estimated (eGFR) with equations based on circulating creatinine or cystatin C levels. However, these equations have not been thoroughly validated in the HTx population.
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| 4. |
- Lee, DM, et al.
(författare)
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Oxidative Stress and Inflammation in Renal Patients and Healthy Subjects
- 2011
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Ingår i: PLOS ONE. - 1932-6203. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- The first goal of this study was to measure the oxidative stress (OS) and relate it to lipoprotein variables in 35 renal patients before dialysis (CKD), 37 on hemodialysis (HD) and 63 healthy subjects. The method for OS was based on the ratio of cholesteryl esters (CE) containing C18/C16 fatty acids (R2) measured by gas chromatography (GC) which is a simple, direct, rapid and reliable procedure. The second goal was to investigate and identify a triacylglycerol peak on GC, referred to as TG48 (48 represents the sum of the three fatty acids carbon chain lengths) which was markedly increased in renal patients compared to healthy controls. We measured TG48 in patients and controls. Mass spectrometry (MS) and MS twice in tandem were used to analyze the fatty acid composition of TG48. MS showed that TG48 was abundant in saturated fatty acids (SFAs) that were known for their pro-inflammatory property. TG48 was significantly and inversely correlated with OS. Renal patients were characterized by higher OS and inflammation than healthy subjects. Inflammation correlated strongly with TG, VLDL-cholesterol, apolipoprotein (apo) C-III and apoC-III bound to apoB-containing lipoproteins, but not with either total cholesterol or LDL-cholesterol.In conclusion, we have discovered a new inflammatory factor, TG48. It is characterized with TG rich in saturated fatty acids. Renal patients have increased TG48 than healthy controls.
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| 5. |
- Albertsson, Per, 1964, et al.
(författare)
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Positron emission tomography and computed tomographic (PET/CT) imaging for radiation therapy planning in anal cancer: A systematic review and meta-analysis
- 2018
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Ingår i: Critical reviews in oncology/hematology. - : Elsevier BV. - 1040-8428. ; 126, s. 6-12
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Forskningsöversikt (refereegranskat)abstract
- To improve the accuracy of chemoradiation therapy in anal cancer patients PET/CT is frequently used in the planning of radiation therapy. A systematic review was performed to assess impact on survival, quality of life, symptom score, change in target definition and treatment intention. Systematic literature searches were conducted in Medline, EMBASE, the Cochrane Library, and Centre for Reviews and Dissemination. Ten cross-sectional studies were identified. No data were available on survival or quality of life. The summary estimate of the proportion of patients in which PET/CT had an impact on the target definition, was 23% (95% CI 16;33). The corresponding summary estimate of a change in treatment intent from curative to palliative was 3% (95% CI 2;6). Almost one in four patients had a change in target definition, which supports the use of PET/CT in radiation therapy planning, but the consequence regarding survival and quality of life is still uncertain.
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| 6. |
- Almgren, Torbjörn, 1959, et al.
(författare)
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Diabetes in treated hypertension is common and carries a high cardiovascular risk: results from a 28-year follow-up.
- 2007
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Ingår i: Journal of hypertension. - 0263-6352. ; 25:6, s. 1311-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The objective of this study was to analyse predictive factors for development of type 2 diabetes during life-long therapy for hypertension and the alleged additional cardiovascular risk this constitutes. METHODS: The study group (n = 754) comprised the hypertensive subgroup of a randomized population sample of 7500 men, aged 47-54 years, screened for cardiovascular risk factors and followed for 25-28 years. The patients were treated with thiazide diuretics and beta-adrenergic blocking drugs with the addition of hydralazin during the first decade. Calcium antagonists were substituted for hydralazin and, if needed, angiotensin-converting enzyme inhibitors were added when these drugs became available. RESULTS: A total of 148 (20.4%) treated hypertensive patients developed diabetes during 25 years, and in multivariate Cox regression analysis body mass index, serum triglycerides and treatment with beta-blockers were positively related with this complication. New-onset diabetes implied a significantly increased risk for stroke [hazard ratio (HR): 1.67; 95% confidence interval (95% CI): 1.1-2.6; P < 0.05], myocardial infarction (OR: 1.66; 95% CI: 1.1-2.5; P < 0.05) and mortality (OR: 1.42; 95% CI: 1.1-1.9; P < 0.05). The greatest risk for stroke was new-onset diabetes, followed by smoking (OR: 1.46; 95% CI: 1-2.2; P = 0.07) and the greatest risk for myocardial infarction was new-onset diabetes, followed by smoking (HR: 1.64; 95% CI: 1.1-2.4; P < 0.01). The greatest risk for mortality was smoking (HR: 1.73; 95% CI: 1.3-2.2; P < 0.005). Achieved systolic and diastolic blood pressure were not predictive of cardiovascular complications or death. The mean observation time from onset of diabetes mellitus to a first stroke was 9.1 years and to a first myocardial infarction 9.3 years. CONCLUSION: Diabetes in treated hypertensive patients is alarmingly common and carries a high risk for cardiovascular complications and mortality.
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| 7. |
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| 8. |
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| 9. |
- Bergh, Christina, 1953, et al.
(författare)
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Regionalt HTA-arbete kan ge bra genomslag i vården. Goda exempel från Västra Götaland : [Regional HTA work can have a good impact on health care. Good examples form Vastra Gotaland].
- 2010
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Ingår i: Läkartidningen. - 0023-7205. ; 107:29-31, s. 1780-1783
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Tidskriftsartikel (refereegranskat)abstract
- HTA (health technology assessment) innebär en systematisk granskning av det vetenskapliga underlaget för en viss teknik. Ett väl definierat PICO (patients, intervention, comparison, outcome) är en grundförutsättning för att få fram den dokumentation som ska granskas. En fokuserad fråga är central i HTA-processen. En teknik granskas med avseende på effektivitet och risker, etiska och organisatoriska aspekter samt kostnader. I en systematisk litteraturöversikt granskas vetenskapliga artiklar med avseende på kvalitet och relevans. Slutsatserna evidensgraderas enligt GRADE. I Västra Götalandsregionen har inrättats ett HTA-centrum som arbetar med regional medicinsk utvärdering. Regionalt HTA-arbete har flera fördelar; en är att den praktiska omsättningen av de nyvunna kunskaperna troligen kan ske snabbare.
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| 10. |
- Bäck, Marcus, et al.
(författare)
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Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease : use of cyclopentane and cyclopentene P2-motifs
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:22, s. 7184-7202
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Tidskriftsartikel (refereegranskat)abstract
- Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a Ki value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Dahlgren, Anders, et al.
(författare)
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Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors : design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex
- 2002
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 10:6, s. 1829-1839
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Tidskriftsartikel (refereegranskat)abstract
- A morpholinone structural motif derived from d(+)- and l(−)-malic acid has been used as a mimic of d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the α-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 720 nM. The X-ray crystal structure of this candidate co-crystallized with α-thrombin is discussed.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Fellström, Bengt, et al.
(författare)
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Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.
- 2009
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Ingår i: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 360:14, s. 1395-407
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. METHODS: We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events. RESULTS: After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51). CONCLUSIONS: In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (ClinicalTrials.gov number, NCT00240331.)
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| 20. |
- Ghali, Jalal K, et al.
(författare)
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The influence of renal function on clinical outcome and response to beta-blockade in systolic heart failure: insights from Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF).
- 2009
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Ingår i: Journal of cardiac failure. - : Elsevier BV. - 1532-8414 .- 1071-9164. ; 15:4, s. 310-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Limited information is available on the risk and impact of renal dysfunction on the response to beta-blockade and mode of death in systolic heart failure (HF). METHODS AND RESULTS: Renal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR(MDRD) > 60 (n = 2496), eGFR(MDRD) 45 to 60 (n = 976), and eGFR(MDRD) < 45 mL/min per 1.73 m(2) body surface area (n = 493). Hazard ratio (HR) was estimated with Cox proportional hazards models adjusted for prespecified risk factors. Placebo patients with eGFR < 45 had significantly higher risk than those with eGFR > 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR < 45 and eGFR > 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR < 45. For total mortality, metoprolol CR/XL vs placebo: HR, 0.41 (95% CI. 0.25 to 0.68; P < .001) in those with eGFR < 45 compared with HR, 0.71 (95% CI, 0.54 to 0.95; P < .021) for those with eGFR > 60; corresponding data for the combined end point was HR, 0.44 (95% CI, 0.31 to 0.63; P < .0001) and HR, 0.75 (0.62 to 0.92; P = .005, respectively; P = .095 for interaction by treatment for total mortality; P = .011 for combined end point). Metoprolol CR/XL was well tolerated in all 3 renal function subgroups. CONCLUSIONS: Renal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR < 45 as in those with eGFR > 60.
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| 21. |
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| 22. |
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| 23. |
- Hallberg, Håkan, et al.
(författare)
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Benefits and risks with acellular dermal matrix (ADM) and mesh support in immediate breast reconstruction: a systematic review and meta-analysis
- 2018
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - 2000-656X .- 2000-6764. ; 52:3, s. 130-147
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Tidskriftsartikel (refereegranskat)abstract
- In modern implant-based immediate breast reconstruction, it has become common to use biological acellular dermal and synthetic matrices in combination with a tissue expander or an implant. The aim of this systematic review was to examine differences in recurrence of cancer, impact on oncological treatment, health related quality of life, complications and aesthetic outcome between matrix and no matrix in immediate breast reconstruction. Systematic searches, data extraction and assessment of methodological quality were performed according to predetermined criteria. Fifty-one studies were eligible and included in the review. The certainty of evidence for overall complication rate and implant loss is low (GRADE ⊕⊕□ □). The certainty of evidence for delay of adjuvant treatment, implant loss, infection, capsular contraction and aesthetic outcome is very low (GRADE ⊕□ □ □). No study reported data on recurrence of cancer or health related quality of life. In conclusion, there is a lack of high quality studies that compare the use of matrix with no matrix in immediate breast reconstruction. Specifically, there are no data on risk of recurrence of cancer, delay of adjuvant treatment and Health related quality of life (HRQoL). In addition, there is a risk of bias in many studies. It is often unclear what complications have been included and how they have been diagnosed, and how and when capsular contracture and aesthetic outcome have been evaluated. Controlled trials that further analyse the impact of radiotherapy, type of matrix and type of procedure (one or two stages) are necessary.
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| 24. |
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| 25. |
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| 26. |
- Hamrén, Bengt, et al.
(författare)
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Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function : evidence of interconversion
- 2008
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 65:6, s. 855-863
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Tidskriftsartikel (refereegranskat)abstract
- AIMS To develop a mechanistic pharmacokinetic (PK) model for tesaglitazar and its metabolite (an acyl glucuronide) following oral administration of tesaglitazar to subjects with varying renal function, and derive an explanation for the increased plasma exposure of tesaglitazar in subjects with impaired renal function. METHODS Data were from a 6-week study in subjects with renal insufficiency and matched controls undergoing repeated oral dosing with tesaglitazar (n = 41). Compartmental population PK modelling was employed to describe the PK of tesaglitazar and its metabolite, in plasma and urine, simultaneously. Two hypotheses were tested to investigate the increased exposure of tesaglitazar in subjects with renal functional impairment: tesaglitazar metabolism is correlated with renal function, or metabolite elimination is reduced in renal insufficiency, leading to increased hydrolysis (interconversion) to the parent compound via biliary circulation. RESULTS The hypothesis for interconversion was best supported by the data. The population PK model included first-order absorption, two-compartment disposition and separate renal (0.027 l h(-1)) and metabolic (1.9 l h(-1)) clearances for tesaglitazar. The model for the metabolite; one-compartment disposition with renal (saturable, V-max = 0.19 mu mol l(-1) and Km = 0.04 mmol l(-1)) and nonrenal clearances (1.2 l h(-1)), biliary secretion (12 h(-1)) to the gut, where interconversion and reabsorption (0.8 h(-1)) of tesaglitazar occurred. CONCLUSION A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite.
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| 27. |
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| 28. |
- Hedner, Thomas, 1949, et al.
(författare)
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Nabumetone: therapeutic use and safety profile in the management of osteoarthritis and rheumatoid arthritis.
- 2004
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Ingår i: Drugs. - : Springer Science and Business Media LLC. - 0012-6667. ; 64:20
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Forskningsöversikt (refereegranskat)abstract
- Nabumetone is a nonsteroidal anti-inflammatory prodrug, which exerts its pharmacological effects via the metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). Nabumetone itself is non-acidic and, following absorption, it undergoes extensive first-pass metabolism to form the main circulating active metabolite (6-MNA) which is a much more potent inhibitor of preferentially cyclo-oxygenase (COX)-2. The three major metabolic pathways of nabumetone are O-demethylation, reduction of the ketone to an alcohol, and an oxidative cleavage of the side-chain occurs to yield acetic acid derivatives. Essentially no unchanged nabumetone and < 1% of the major 6-MNA metabolite are excreted unchanged in the urine from which 80% of the dose can be recovered and another 10% in faeces. Nabumetone is clinically used mainly for the management of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) to reduce pain and inflammation. The clinical efficacy of nabumetone has also been evaluated in patients with ankylosing spondylitis, soft tissue injuries and juvenile RA. The optimum oral dosage of nabumetone for OA patients is 1 g once daily, which is well tolerated. The therapeutic response is superior to placebo and similar to nonselective COX inhibitors. In RA patients, nabumetone 1 g at bedtime is optimal, but an additional 0.5-1 g can be administered in the morning for patients with persistent symptoms. In RA, nabumetone has shown a comparable clinical efficacy to aspirin (acetylsalicylic acid), diclofenac, piroxicam, ibuprofen and naproxen. Clinical trials and a decade of worldwide safety data and long-term postmarketing surveillance studies show that nabumetone is generally well tolerated. The most frequent adverse effects are those commonly seen with COX inhibitors, which include diarrhoea, dyspepsia, headache, abdominal pain and nausea. In common with other COX inhibitors, nabumetone may increase the risk of GI perforations, ulcerations and bleedings (PUBs). However, several studies show a low incidence of PUBs, and on a par with the numbers reported from studies with COX-2 selective inhibitors and considerably lower than for nonselective COX inhibitors. This has been attributed mainly to the non-acidic chemical properties of nabumetone but also to its COX-1/COX-2 inhibitor profile. Through its metabolite 6-MNA, nabumetone has a dose-related effect on platelet aggregation, but no effect on bleeding time in clinical studies. Furthermore, several short-term studies have shown little to no effect on renal function. Compared with COX-2 selective inhibitors, nabumetone exhibits similar anti-inflammatory and analgesic properties in patients with arthritis and there is no evidence of excess GI or other forms of complications to date.
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| 29. |
- Hrafnkelsdottir, Thordis, 1965, et al.
(författare)
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Impaired endothelial release of tissue-type plasminogen activator in patients with chronic kidney disease and hypertension
- 2004
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Ingår i: Hypertension. - 1524-4563. ; 44:3, s. 300-4
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Tidskriftsartikel (refereegranskat)abstract
- We have shown that the capacity for local release of tissue-type plasminogen activator (tPA) from the vascular endothelium is impaired in patients with primary hypertension. Because this response is an important protective mechanism against intravascular clotting, we investigated whether this system is also defective in patients with advanced chronic kidney disease and hypertension. Nine nondiabetic nonsmoking men with chronic kidney disease (glomerular filtration rate 11 to 28 mL/min x 1.73 m2; aged 33 to 75 years) were compared with age-matched healthy controls. Intraarterial infusions of desmopressin, methacholine, and sodium nitroprusside were given locally in the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography and blood collected repeatedly during the desmopressin infusion for determination of stimulated net and total cumulated release of tPA. The maximal release rate of active tPA (P<0.05) and the capacity for acute tPA release were markedly impaired in the renal patients as compared with healthy subjects (ANOVA, P=0.013). Accordingly, the accumulated release of tPA was 1905 (SEM 366) and 3387 (718) ng/L tissue, respectively (P<0.05). However, there were no significant differences in vasodilator responses between the groups. Thus, patients with advanced chronic kidney disease and hypertension have a markedly impaired capacity for acute release of tissue plasminogen activator, despite preserved endothelium-dependent vasodilation. This defect may contribute to a defective local defense against arterial thrombosis.
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| 30. |
- Johansson, Per-Ola, et al.
(författare)
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Design and synthesis of potent inhibitors of plasmepsin I and II : x-ray crystal structure of inhibitor in complex with plasmepsin II
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:13, s. 4400-4409
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Tidskriftsartikel (refereegranskat)abstract
- New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.
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| 31. |
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| 32. |
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| 33. |
- Johansson, Per-Ola, et al.
(författare)
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Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II : Use of solid-phase synthesis to explore novel statine motifs
- 2004
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:13, s. 3353-3366
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Tidskriftsartikel (refereegranskat)abstract
- Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 μM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.
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| 34. |
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| 35. |
- Kolsrud, Oscar, et al.
(författare)
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Renal function and outcome after heart transplantation
- 2018
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier BV. - 0022-5223. ; 155:4
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate whether measured glomerular filtration rate (mGFR) is a risk factor for death and/or end-stage renal disease (ESRD) after heart transplantation (HTx). Methods: All adult patients (n = 416) who underwent HTx between 1988 and 2010 were included. mGFR was performed both preoperatively and postoperatively as annual follow-up. Eight patients received a concomitant kidney transplant (KTx), and 15 underwent late KTx due to chronic renal failure after HTx. Results: The mean drop in mGFR compared with the preoperative value was 12% during the first year after HTx. Preoperative mGFR was not predictive of mortality or ESRD. Older or the use of a ventricular assist device (VAD) were preoperative predictors of death. Long-term survival was significantly worse in the patients who experienced a >25% decrease in mGFR during the first year after transplantation. The need for acute postoperative renal replacement therapy (RRT) was associated with impaired survival but did not predict ESRD among survivors. On multivariable analyses, previous heart surgery, preoperative VAD, and a lower mGFR were all predictors of RRT. In the most recent period, death without previous ESRD was lower, and the only preoperative factors associated with ESRD by multivariable analyses were mechanical ventilation and diabetes mellitus. Conclusions: Pretransplantation mGFR was not predictive of mortality or ESRD after HTx, but necessitated simultaneous or late-stage KTx in this selected population of patients. However, patients with a decrease in >25% mGFR during the first year post-transplantation, as well as early postoperative dialysis-dependent acute renal dysfunction, had a poor prognosis. We suggest that patients with severely impaired kidney function, irrespective of pretransplantation renal function, still should be considered for HTx, but also encourage careful interpretation of our results given the selection bias involved in this population.
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| 36. |
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| 37. |
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| 38. |
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| 39. |
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| 40. |
- Lindholm, Lars H, et al.
(författare)
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Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).
- 2003
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 21:8, s. 1563-74
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation study was to compare the long-term effect of the commonly used inexpensive medication with a low-dose diuretic (hydrochlorothiazide), alone or in combination with a beta-adrenoceptor (atenolol), with that of more modern but also more expensive antihypertensive treatment with an angiotensin-II-receptor blocker (candesartan), alone or in combination with a calcium antagonist (felodipine), and to do so in newly diagnosed patients with primary hypertension. The objectives included comparisons of the effects on the glucose metabolism, lipoprotein metabolism, electrolytes, blood pressure, and subjective symptoms.DESIGN: A 1-year, prospective randomized, double-blind, controlled trial.SUBJECTS: In an investigator-initiated study, we included 392 patients (mean age 55 years, 48% men); 370 patients (94%) had never been treated with antihypertensive drugs before the study. No patient was lost to follow-up.RESULTS: Both treatment regimens lowered blood pressure well (23/13 mmHg in the hydrochlorothiazide group and 21/13 mmHg in the candesartan group), with a majority of patients needing two drugs. Fasting levels of both serum insulin and plasma glucose increased in the hydrochlorothiazide group in contrast to unaffected levels in the candesartan group. Diabetes mellitus was diagnosed in nine patients during follow-up, in eight patients in the hydrochlorothiazide group (4.1%) and in one patient (0.5%) in the candesartan group (P = 0.030). Triglycerides increased and high-density lipoprotein-cholesterol decreased more in the hydrochlorothiazide group than in the candesartan group. Both the low-density lipoprotein/high-density lipoprotein and the apolipoprotein B/apolipoprotein A-I ratios increased in the hydrochlorothiazide group. At 12 months, 18 patients in the hydrochlorothiazide group versus five in the candesartan group had a 'metabolic syndrome', as defined by the World Health Organization (P = 0.007) despite 1 year of active blood pressure-lowering therapy. There were less (P = 0.020) adverse events in the candesartan group, but no major differences in the subjective symptoms assessment profile. One subject in each group had a myocardial infarction.CONCLUSION: Antihypertensive treatment with a diuretic, if needed combined with a beta-adrenoceptor blocker, was associated with an aggravated metabolic profile; this was not so for patients treated with an angiotensin-II-receptor blocker, if needed combined with a calcium antagonist. An antihypertensive treatment strategy that costs more in the short run but has no metabolic adverse effects may have a health economic impact in the long term.
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| 41. |
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| 42. |
- Magnéli, Martin, et al.
(författare)
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Only 8% of major preventable adverse events after hip arthroplasty are filed as claims : a Swedish multi-center cohort study on 1,998 patients
- 2020
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Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 91:1, s. 20-25
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose — Hip arthroplasty is one of the most performed surgeries in Sweden, and the rate of adverse events (AEs) is fairly high. All patients in publicly financed healthcare in Sweden are insured by the Mutual Insurance Company of Swedish County Councils (Löf). We assessed the proportion of patients that sustained a major preventable AE and filed an AE claim to Löf. Patients and methods — We performed retrospective record review using the Global Trigger Tool to identify AEs in a Swedish multi-center cohort consisting of 1,998 patients with a total or hemi hip arthroplasty. We compared the major preventable AEs with all patient-reported claims to Löf from the same cohort and calculated the proportion of filed claims. Results — We found 1,066 major preventable AEs in 744 patients. Löf received 62 claims for these AEs, resulting in a claim proportion of 8%. 58 of the 62 claims were accepted by Löf and received compensation. The claim proportion was 13% for the elective patients and 0.3% for the acute patients. The most common AE for filing a claim was periprosthetic joint infection; of the 150 infections found 37 were claimed. Interpretation — The proportion of filed claims for major preventable AEs is very low, even for obvious and serious AEs such as periprosthetic joint infection.
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| 43. |
- Magnéli, Martin, et al.
(författare)
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Validation of adverse events after hip arthroplasty : a Swedish multi-centre cohort study.
- 2019
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Preventing adverse events (AEs) after orthopaedic surgery is a field with great room for improvement. A Swedish instrument for measuring AEs after hip arthroplasty based on administrative data from the national patient register is used by both the Swedish Hip Arthroplasty Register and the Swedish Association of Local Authorities and Regions. It has never been validated and its accuracy is unknown. The aim of this study was to validate the instrument's ability to detect AEs, and to calculate the incidence of AEs following primary hip arthroplasties.DESIGN: Retrospective cohort study using retrospective record review with Global Trigger Tool methodology in combination with register data.SETTING: 24 different hospitals in four major regions of Sweden.PARTICIPANTS: 2000 patients with either total or hemi-hip arthroplasty were recruited from the SHAR. We included both acute and elective patients.PRIMARY AND SECONDARY OUTCOME MEASURES: The sensitivity and specificity of the instrument. Adjusted cumulative incidence and incidence rate.RESULTS: The sensitivity for all identified AEs was 5.7% (95% CI: 4.9% to 6.7%) for 30 days and 14.8% (95% CI: 8.2 to 24.3) for 90 days, and the specificity was 95.2% (95% CI: 93.5% to 96.6%) for 30 days and 92.1% (95% CI: 89.9% to 93.8%) for 90 days. The adjusted cumulative incidence for all AEs was 28.4% (95% CI: 25.0% to 32.3%) for 30 days and 29.5% (95% CI: 26.0% to 33.8%) for 90 days. The incidence rate was 0.43 AEs per person-month (95% CI: 0.39 to 0.47).CONCLUSIONS: The AE incidence was high, and most AEs occurred within the first 30 days. The instrument sensitivity for AEs was very low for both 30 and 90 days, but the specificity was high for both 30 and 90 days. The studied instrument is insufficient for valid measurements of AEs after hip arthroplasty.
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| 44. |
- Mårald, Erland, et al.
(författare)
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Exploring the use of a dialogue process to tackle a complex and controversial issue in forest management
- 2015
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Ingår i: Scandinavian Journal of Forest Research. - : Informa UK Limited. - 0282-7581 .- 1651-1891. ; 30:8, s. 749-756
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Tidskriftsartikel (refereegranskat)abstract
- This article explores the use of a dialogue process to approach complex issues related to forest management. Aninterdisciplinary research team set up an experimental dialogue process concerning the use of introduced tree speciesin Southern Sweden for the purposes of climate change adaptation. The process involved stakeholders at a regionallevel, including those with divergent opinions regarding introduced tree species and their use in forestry. Through aprocess of repeated meetings and exchanges with researchers, the participant’s knowledge was deepened and grouprelationships developed such that the group was able to jointly formulate a set of policy recommendations. Theinvestigation revealed that dialogue processes may improve decision-making by identifying priorities for action orfurther research. However, when a collaborative process targets complex environmental issues on larger geographicaland temporal scales, as matters about forests typically do, a collaborative process must be integrated with externalactors and institutions in order to attain tangible outcomes. Consequently, to fully access the benefits of usingcollaborative processes to handle complex challenges in forest policy and management, the connections betweenpolitical sphere, the private sector, authorities and research institutions must be concretely established.
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| 45. |
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| 46. |
- Nordén, Gunnela, 1945, et al.
(författare)
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ABO-incompatible live donor renal transplantation using blood group A/B carbohydrate antigen immunoadsorption and anti-CD20 antibody treatment.
- 2006
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Ingår i: Xenotransplantation. - : Wiley. - 0908-665X .- 1399-3089. ; 13:2, s. 148-53
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Blood group ABO-incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO-incompatible LD renal transplantation using specific anti-A/B antibody (Ab) immunoadsorption (IA) and anti-CD20 monoclonal Ab (mAb) treatment. PATIENTS AND TREATMENT PROTOCOL: Recipients were blood group O (n = 12), A (n = 1) and B (n = 1). Donors were A1 (n = 2), A2 (n = 3), A2B (n = 1) and B (n = 8), and all were secretor positive. Anti-human leukocyte antigen (HLA) Ab panel reactivity was negative in all recipients except one. All recipients were pre-treated with 3 to 6 IA sessions, using A or B carbohydrate antigen columns, until their anti-A1/B RBC panel indirect antiglobulin test (IAT) titers were < or =8. CDC crossmatch was negative in all cases. Recipients received preoperative mycophenolic acid, and steroids/tacrolimus were started at transplantation. No splenectomy was performed. Eight recipients received one dose of anti-CD20 mAb (rituximab, 375 mg/m2) pre-operatively and 11 recipients had postoperative protocol IA. RESULTS: In the initial protocol, anti-CD20 mAbs were used only for recipients receiving A1 grafts. One B graft (HLA-identical donor, 84% panel reactivity) was lost in a severe anti-B Ab-mediated acute rejection. Subsequently, the protocol included anti-CD20 for recipients of both A1 and B grafts and postoperative protocol IA to all recipients. The subsequent 10 grafts had excellent function, giving a total graft survival of 13/14 (observation range 2 to 41 months). At 1 yr, mean serum creatinine was 113 micromol/l (n = 8) and mean glomerular filtration rate was 55 ml/min/1.73 m2 (range 24 to 77). In the remaining five cases, with less than 1 yr follow up, mean serum creatinine was 145 micromol/l at 2 to 9 months follow up. Pre-IA anti-A/B titers were in the range of 2 to 32 (NaCl technique) and 16 to 512 (IAT). More than 90 IA sessions were performed in 14 recipients without any significant side effects. Recipient anti-A/B titers returned after transplantation to pre-IA levels or slightly lower. Postoperative renal biopsies were performed in 10 patients. In the 13 patients with long-term function, one patient experienced cellular rejection (Banff IIB) at 3 months without anti-B titer rise. This rejection was concomitant with low tacrolimus plasma levels and was easily reversed by steroids. In 8 of 10 cases, C4d staining was positive in peritubular capillaries. CONCLUSION: Blood group ABO-incompatible LD renal transplantation using A and B carbohydrate-specific IA and anti-CD20 mAbs has excellent graft survival and function.
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| 47. |
- Raja, Visakha, 1985, et al.
(författare)
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Exploring Influence of Static Engine Component Design Variables on System Level Performance
- 2015
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Ingår i: 22nd International Symposium on Air Breathing Engines, ISABE2015.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- To reach even better operating efficiency and reduced fuel burn, aero engine manufacturers adopt various innovative design methods. Many of the design methods rely on more integrated component and engine design. This makes it necessary for component suppliers such as GKN to be involved more tightly in the design process with the engine integrator. It also necessitates the need for the component developer to predict the effects that its components produce at the engine level so that the designs can be better prepared for future engine architectures. In this paper, an integrated design method is used to make preliminary exploration of the effect of aero-engine static structure design variations on engine performance. Studies were performed on a turbine rear structure (TRS) which is a part of the low pressure (LPT) turbine module. Pressure losses from an aerodynamically well designed TRS (with good LPT outflow match) and a poor LPT outflow matched TRS were coupled to an engine performance model to simulate the effect on engine SFC. The effect on engine SFC due to poor LPT outflow matched TRS coupling is more pronounced than that for aerodynamically well designed TRS. Also pressure drops for an aerodynamically well designed TRS are themselves dependant on structural design variations such as changes in geometrical variables. In this case, the influence of component design variation on SFC is substantial and the relevance of an integrated engine-component design is apparent. Judging from the preliminary findings it can be concluded that additional studies with more variables coupled can reveal further dependencies between engine and the component which are previously un-explored. This seeks to motivate the development of methods to create a multi-level, multi-physics optimization platform for hot engine structures which is the future aim of the project as a part of which this study was conducted.
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| 48. |
- Rist, Lucy, et al.
(författare)
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A new paradigm for adaptive management
- 2013
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Ingår i: Ecology and Society. - 1708-3087. ; 18:4, s. 63-
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Tidskriftsartikel (refereegranskat)abstract
- Uncertainty is a pervasive feature in natural resource management. Adaptive management, an approach that focuses on identifying critical uncertainties to be reduced via diagnostic management experiments, is one favored approach for tackling this reality. While adaptive management is identified as a key method in the environmental management toolbox, there remains a lack of clarity over when its use is appropriate or feasible. Its implementation is often viewed as suitable only in a limited set of circumstances. Here we restructure some of the ideas supporting this view, and show why much of the pessimism around AM may be unwarranted. We present a new framework for deciding when AM is appropriate, feasible, and subsequently successful. We thus present a new paradigm for adaptive management that shows that there are no categorical limitations to its appropriate use, the boundaries of application being defined by problem conception and the resources available to managers. In doing so we also separate adaptive management as a management tool, from the burden of failures that result from the complex policy, social, and institutional environment within which management occurs.
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| 49. |
- Rist, Lucy, et al.
(författare)
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Avoiding the pitfalls of adaptive management implementation in Swedish silviculture
- 2016
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 45, s. 140-151
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Tidskriftsartikel (refereegranskat)abstract
- There is a growing demand for alternatives to Sweden’s current dominant silvicultural system, driven by a desire to raise biomass production, meet environmental goals and mitigate climate change. However, moving towards diversified forest management that deviates from well established silvicultural practices carries many uncertainties and risks. Adaptive management is often suggested as an effective means of managing in the context of such complexities. Yet there has been scepticism over its appropriateness in cases characterised by large spatial extents, extended temporal scales and complex land ownership—characteristics typical of Swedish forestry. Drawing on published research, including a new paradigm for adaptive management, we indicate how common pitfalls can be avoided during implementation. We indicate the investment, infrastructure, and considerations necessary to benefit from adaptive management. In doing so, we show how this approach could offer a pragmatic operational model for managing the uncertainties, risks and obstacles associated with new silvicultural systems and the challenges facing Swedish forestry.
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| 50. |
- Rydberg, Lennart, 1944, et al.
(författare)
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In vitro assessment of a new ABO immunosorbent with synthetic carbohydrates attached to sepharose.
- 2005
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Ingår i: Transplant international : official journal of the European Society for Organ Transplantation. - : Frontiers Media SA. - 0934-0874. ; 17:11, s. 666-72
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation across the ABO barrier is sometimes done in cases of emergency, such as acute liver failure, but is also carried out in elective cases, e.g. kidneys from living donors. Reducing the recipient anti-A/B antibody titres is often necessary in ABO-incompatible kidney transplantation. This is usually done by the use of techniques such as plasmapheresis and protein A- or sepharose-linked anti-human Ig immunoadsorption. A new ABO immunosorbent with synthetic A- or B-trisaccharide carbohydrate epitopes linked to a sepharose matrix has been tested. Columns made of this material have been tested in vitro with plasma from A- and B-individuals, assessed for antibody reduction capacity, flow characteristics, biocompatibility, and unspecific protein adsorption. The columns have a high capacity for ABO antibody removal, reducing titres by three to seven steps in one passage. We noted a high biocompatibility, with no unspecific protein adsorption, no activation of coagulation factors, and a low activation of complement, no immune complex formation and no cytotoxicity towards cultured mammalian L929 cells.
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