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- Alattar, AG, et al.
(författare)
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Gene editing of CD34+ progenitor cells from single blood donor waste bags to create cultured early erythroid cells for study of blood group knock-outs
- 2020
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Ingår i: Vox Sanguinis. - : Wiley. - 1423-0410 .- 0042-9007. ; 115:Suppl. s1, s. 363-363
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Konferensbidrag (refereegranskat)abstract
- Background: Many blood group antigens are carried by red cell surface proteins, thefunctions of which are not yet fully characterized or in some cases completelyunknown. By investigating red cells with naturally-occurring blood group variants,much has been learnt about the underlying molecules. However, interindividualvariation affecting other molecules than the one(s) of interest may confound orotherwise hamper such studies. As an alternative, a reductionistic approach whereonly a single factor differs between test and control cells significantly facilitatesinterpretation of functional studies. Using various siRNA, shRNA and various gene-editing tools blood group expression can be manipulated and useful modelsdeveloped. Applying the latter on primary hematopoietic stem and progenitor cells(HSPCs) can be challenging.Aims: We evaluated a protocol for gene editing of CD44 using a CRISPR/Cas9hybrid system on HSPCs isolated from blood donation leukocyte waste bags fromsingle donors to develop a model for study of blood group molecular function inerythropoiesis.Methods: Peripheral blood mononuclear cells (PBMCs) were from anonymizedleucocyte waste bags obtained after whole blood unit processing in the Reveosautomated blood component system. Cells were harvested following Lymphoprepgradient separation and CD34+HSPCs enriched and collected using magnetic beads.CD34+cells were cultured in 2-phase culture medium to generate erythroid cellsfrom HSPCs (Vidovic, Vox Sang 2017). For CRISPR/Cas9 gene editing, a short guideRNA (sgRNA) targeting CD44 was designed and cloned into the lentiCRISPR v2vector (Addgene plasmid #52961). A non-targeting sgRNA cloned into the vectorwas used as control. Lentivirus particles were produced in the human 293T cell lineas described previously (Galeev, Methods Mol Biol 2017). Equal number of CD34+cells were transduced 24 hours after collection using RetroNectin following theRetroNectin-Bound Virus (RBV) Infection Method according to manufacturer’sprotocol. Cells were transduced at a multiplicity of infection (MOI) of 10 with atarget transduction efficiency of 20–30%. Cells were cultured at 37°C, 5% CO2 for72 hours in phase I culture medium and then electroporated with Cas9 mRNA usingthe ECM 830 Electroporation System as described previously for cord blood-derivedCD34+cells (Backstrom, Exp Hematol 2019). GFP+CD44-edited cell frequencieswere monitored by flow cytometry at day 7 of the HSPC expansion phase and atday 14 of the erythroid expansion-differentiation phase using antibodies againsterythroid-specific cell surface markers GPA and Band3 in addition to CD49d toassess the erythroid development stage.Results: We tested the above protocol and observed that the frequencies of editedcells lacking CD44 expression within the GFP+population at day 7 of culture were10–25% while the edited frequencies were increased at day 14 of culture to 60–80%within the GFP+cells. Whilst this stage corresponds to erythroblasts, earlier or laterstages can be tested.Summary/Conclusions: The previously established hybrid system for CRISPR/Cas9gene editing in cord blood-derived CD34+HSPCs, which combines lentiviraldelivery of the sgRNA with transient delivery of Cas9 mRNA by electroporation, isalso applicable to primary human adult HSPCs from Reveos-processed single-donorwhole blood donation, resulting in a traceable high-yield gene-editing system tostudy blood group function and erythroid development
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- Ekeström, ML, et al.
(författare)
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Family members' experiences of the impact of the LCP in a palliative care unit and a geriatric ward in Sweden
- 2014
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Ingår i: International journal of palliative nursing. - : Mark Allen Group. - 1357-6321 .- 2052-286X. ; 20:8, s. 381-6
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Tidskriftsartikel (refereegranskat)abstract
- The Liverpool Care Pathway for the Dying Patient (LCP) was developed to transfer palliative care standards for the last hours or days of life, including family support, from hospice to other care settings. Aim: This study sought to explore family members' experiences of end-of-life care in a palliative care unit and in a general geriatric ward in Sweden before and after implementation of the LCP. Methods: Experiences were evaluated in relation to the goals of the LCP. Family members of patients deceased before and after implementation answered a questionnaire 3–6 months after the death. Comparisons between the samples were assessed by non-parametric tests. Results: There were significant differences concerning dialogue about existential issues that arise and about emotions and practical issues faced in bereavement. Significant improvements after the implementation of the LCP were reported in experiences regarding physicians' ability to listen to family members' concerns. Conclusion: The results suggest that using a structure such as that provided by the LCP may improve communication between physicians and the families of dying patients.
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| 23. |
- Hedstrom, AK, et al.
(författare)
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Smokers run increased risk of developing anti-natalizumab antibodies
- 2014
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 20:8, s. 1081-1085
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Tidskriftsartikel (refereegranskat)abstract
- Smoking may contribute to the induction of neutralizing antibodies to interferon β-1a. Objective: In this study, we aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of multiple sclerosis. Methods: This report is based on 1338 natalizumab-treated multiple sclerosis patients included in either of two Swedish case-control studies in which information on smoking habits was collected. Using logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies, by calculating odds ratios with 95% confidence intervals. Results: Compared with nonsmokers, the odds ratio of developing anti-natalizumab antibodies was 2.4 (95% CI 1.2–4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking. When smoking within two years prior to screening was considered, the odds ratio of developing anti-natalizumab antibodies was 2.7 (1.5–5.1). Interpretations: The finding strengthens our hypothesis of the lungs as immune-reactive organs on irritation in relation to autoimmune responses, and may also be of clinical relevance since antibodies against natalizumab abrogate the therapeutic effect of the treatment.
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- Khademi, M, et al.
(författare)
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Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course
- 2011
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 17:3, s. 335-343
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Tidskriftsartikel (refereegranskat)abstract
- Background: Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the cerebrospinal fluid (CSF) during multiple sclerosis (MS) and are associated with markers of MS activity. Levels decrease upon effective treatments. Objective: Here we validate the potential role of CSF CXCL13 as a biomarker for aspects of MS in a large amount of clinical material, the majority collected at early diagnostic work-up. Methods: CXCL13 was measured by ELISA in 837 subjects: relapsing–remitting MS (RRMS; n = 323), secondary progressive MS (SPMS; n = 40), primary progressive MS (PPMS; n = 24), clinically isolated syndrome (CIS; n = 79), other neurological diseases (ONDs; n = 181), ONDs with signs of inflammation or viral/bacterial infections (iONDs; n = 176) and healthy controls ( n = 14). Results: Subjects with viral/bacterial infections had extremely high CXCL13 levels compared to all included groups ( p < 0.0001). CXCL13 was otherwise significantly higher in MS compared to the remaining controls ( p < 0.0001), and CIS ( p < 0.01). A significant and positive correlation between CXCL13 and relapse rate, the results obtained for the Expanded Disability Status Scale (EDSS) and the number of lesions detected by MRI was demonstrated. CXCL13 was increased in CIS conversion to clinically definite MS ( p < 0.001). Oligoclonal immunoglobulin band (OCB)-positive CIS or MS had significantly increased CXCL13 levels compared to OCB-negative CIS or MS ( p < 0.001 and p < 0.0001, respectively). Conclusion: CXCL13 was associated with disease exacerbations and unfavourable prognosis in RRMS. Increased CXCL13 was not specific for MS since subjects with viral/bacterial infections exhibited even higher levels. High levels predicted CIS conversion to MS. We suggest that measurement of CSF CXCL13 can be part of the armamentarium in the diagnostic and prognostic work-up in MS and be of help in future treatment decisions.
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| 32. |
- Olsson, IG, et al.
(författare)
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Adolescent depression and stressful life events - A case-control study within diagnostic subgroups
- 1999
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Ingår i: NORDIC JOURNAL OF PSYCHIATRY. - : SCANDINAVIAN UNIVERSITY PRESS. ; 53:5
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Life events in depressed adolescents were studied in a case-control design. A total population of 16- to 17-year-old students in the Ist year of high school were screened for depression (n = 2300). Every student with indication of depression and one cont
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| 33. |
- Pedersen, T R, et al.
(författare)
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High-dose atorvastatin vs usual dose simvastatin for secondary prevention after myocardial infarction - The IDEAL study: A randomized controlled trial
- 2005
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 294:19, s. 2437-2445
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Tidskriftsartikel (refereegranskat)abstract
- Context Evidence suggests that more intensive lowering of low-density lipoprotein cholesterol (LDL-C) than is commonly applied clinically will provide further benefit in stable coronary artery disease. Objective To compare the effects of 2 strategies of lipid lowering on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI). Design, Setting, and Participants The IDEAL study, a prospective, randomized, open-label, blinded end-point evaluation trial conducted at 190 ambulatory cardiology care and specialist practices in northern Europe between March 1999 and March 2005 with a median follow-up of 4.8 years, which enrolled 8888 patients aged 80 years or younger with a history of acute MI. Interventions Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/d; n=4439), or usual-dose simvastatin (20 mg/d; n=4449). Main Outcome Measure Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. Results During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% Cl, 0.78-1.01; P=.07). Nonfatal acute MI occurred in 321 (7.2%) and M7 (6.0%) in the 2 groups (HR, 0.83; 95% Cl, 0.71-0.98; P=.02), but no differences were seen in the 2 other components of the primary end point. Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% Cl, 0.77-0.98; P=.02). Occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (HR, 0.84; 95% Cl, 0.76-0.91; Pless than.001). Non-cardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the 2 groups (HR, 0.92; 95% Cl, 0.73-1.15; P=.47). Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% Cl, 0.85-1.13; P=.81). Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (Pless than.001). Serious myopathy and rhabdomyolysis were rare in both groups. Conclusions In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions.
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| 39. |
- Sugars, R, et al.
(författare)
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Expression of HMGB1 during tooth development
- 2007
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Ingår i: Cell and tissue research. - : Springer Science and Business Media LLC. - 0302-766X .- 1432-0878. ; 327:3, s. 511-519
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Tidskriftsartikel (refereegranskat)
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