| 211. |
- Abdul-Hussein, Saba
(författare)
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Cellular studies of neuromuscular disorders related to the sarcomeric proteins
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sarcomere is the basic unit of cardiac and skeletal muscle contraction and its proper function requires an invariant organization of this structure. Mutations in sarcomeric proteins are known to cause increasing number of different cardiac and skeletal muscle diseases. The front line in research on muscle diseases is at present to define the genetic background and pathogenesis of these diseases. The potential for development of effective therapies depends on elucidation of the molecular and cellular impact of the mutations on morphological abnormalities and muscle weakness that accompany pathogenesis. In paper I we identified an unexpected skeletal muscle myopathy in an infant with fatal cardiomyopathy due to a homozygous mutation in MyBPC3. The ectopic expression of cardiac MyBPC was restricted to abnormal type 1 muscle fibres, indicating that the muscle pathology was caused by a dominate-negative effect of mutant MyBPC3. In paper II we addressed the expression profile of a panel of sarcomeric components during myogenesis, with a focus on proteins associated with a group of congenital disorders. The analyses were performed in cultured human skeletal muscle myoblasts and myotubes. We identified early expression of certain isoforms involved in congenital diseases, suggesting the possibility of an early role for these proteins as constituent of the developing contractile apparatus during myofibrillogenesis. In paper III we used human tissue-culture cells as a model to investigate the primary trigger for β-tropomyosin-related myopathies and the basis for the histological changes seen in muscle biopsies of patients. Protein localization and pathobiology caused by dominant TPM2 mutations were investigated by transfecting human myoblasts and C2C12 with WT and mutant EGFP-fusion β-TM constructs. Abnormal aggregation of β-TM variants and their localization within the thin filaments was observed in myoblasts and differentiated myotubes. We demonstrated that histopathological phenotypes associated with β-TM mutants might be accounted for the variable response to the cellular environment influenced by physiological context, in combination with the time course of expression of mutant protein rather than the alteration of amino acid itself. Our results confirmed that cell cultures of human skeletal muscle are an appropriate tool and environment closer to the reality in human skeletal muscle and more reliably mimic the disease conditions. In paper IV we identified and characterized a new human protein aggregate myopathy and cardiomyopathy associated with combined mutations in isogenes TRIM63 and TRIM54, encoding muscle specific ring finger proteins, MuRF1 and MuRF3, respectively. Our morphological and cellular investigation suggested that the disease is caused through impaired organization of the microtubule network and sarcomeric M-band proteins. The results from this study have deepened the understanding of pathogenesis of a group of sarcomeric
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| 212. |
- Abdul-Hussein, Saba, et al.
(författare)
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Expression profiles of muscle disease-associated genes and their isoforms during differentiation of cultured human skeletal muscle cells
- 2012
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Ingår i: BMC Musculoskeletal Disorders. - : BioMed Central. - 1471-2474. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The formation of contractile myofibrils requires the stepwise onset of expression of muscle specific proteins. It is likely that elucidation of the expression patterns of muscle-specific sarcomeric proteins is important to understand muscle disorders originating from defects in contractile sarcomeric proteins.METHODS: We investigated the expression profile of a panel of sarcomeric components with a focus on proteins associated with a group of congenital disorders. The analyses were performed in cultured human skeletal muscle cells during myoblast proliferation and myotube development.RESULTS: Our culture technique resulted in the development of striated myotubes and the expression of adult isoforms of the sarcomeric proteins, such as fast TnI, fast TnT, adult fast and slow MyHC isoforms and predominantly skeletal muscle rather than cardiac actin. Many proteins involved in muscle diseases, such as beta tropomyosin, slow TnI, slow MyBPC and cardiac TnI were readily detected in the initial stages of muscle cell differentiation, suggesting the possibility of an early role for these proteins as constituent of the developing contractile apparatus during myofibrillogenesis. This suggests that in disease conditions the mechanisms of pathogenesis for each of the mutated sarcomeric proteins might be reflected by altered expression patterns, and disturbed assembly of cytoskeletal, myofibrillar structures and muscle development.CONCLUSIONS: In conclusion, we here confirm that cell cultures of human skeletal muscle are an appropriate tool to study developmental stages of myofibrillogenesis. The expression of several disease-associated proteins indicates that they might be a useful model system for studying the pathogenesis of muscle diseases caused by defects in specific sarcomeric constituents.
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| 213. |
- Abdul-Hussein, Saba, et al.
(författare)
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Phenotypes of Myopathy-Related Beta-Tropomyosin Mutants in Human and Mouse Tissue Cultures
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in TPM2 result in a variety of myopathies characterised by variable clinical and morphological features. We used human and mouse cultured cells to study the effects of beta-TM mutants. The mutants induced a range of phenotypes in human myoblasts, which generally changed upon differentiation to myotubes. Human myotubes transfected with the E41K-beta-TMEGFP mutant showed perinuclear aggregates. The G53ins-beta-TMEGFP mutant tended to accumulate in myoblasts but was incorporated into filamentous structures of myotubes. The K49del-beta-TMEGFP and E122K-beta-TMEGFP mutants induced the formation of rod-like structures in human cells. The N202K-beta-TMEGFP mutant failed to integrate into thin filaments and formed accumulations in myotubes. The accumulation of mutant beta-TMEGFP in the perinuclear and peripheral areas of the cells was the striking feature in C2C12. We demonstrated that human tissue culture is a suitable system for studying the early stages of altered myofibrilogenesis and morphological changes linked to myopathy-related beta-TM mutants. In addition, the histopathological phenotype associated with expression of the various mutant proteins depends on the cell type and varies with the maturation of the muscle cell. Further, the phenotype is a combinatorial effect of the specific amino acid change and the temporal expression of the mutant protein.
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| 214. |
- Abdul-Rahim, A. H., et al.
(författare)
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Risk of stroke in chronic heart failure patients with preserved ejection fraction, but without atrial fibrillation: analysis of the CHARM-Preserved and I-Preserve trials
- 2017
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 38:10, s. 742-750
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Tidskriftsartikel (refereegranskat)abstract
- Aims The incidence and predictors of stroke in patients with heart failure and preserved ejection fraction (HF-PEF), but without atrial fibrillation (AF), are unknown. We described the incidence of stroke in HF-PEF patients with and without AF and predictors of stroke in those without AF. Methods and results We pooled data from the CHARM-Preserved and I-Preserve trials. Using Cox regression, we derived a model for stroke in patients without AF in this cohort and compared its performance with a published model in heart failure patients with reduced ejection fraction (HF-REF)-predictive variables: age, body mass index, New York Heart Association class, history of stroke, and insulin-treated diabetes. The two stroke models were compared and Kaplan-Meier curves for stroke estimated. The risk model was validated in a third HF-PEF trial. Of the 6701 patients, 4676 did not have AF. Stroke occurred in 124 (6.1%) with AF and in 171 (3.7%) without AF (rates 1.80 and 1.00 per 100 patient-years, respectively). There was no difference in performance of the stroke model derived in the HF-PEF cohort and the published HF-REF model (c-index 0.71, 95% confidence interval 0.57-0.84 vs. 0.73, 0.59-0.85, respectively) as the predictive variables overlapped. The model performed well in the validation cohort (0.86, 0.62-0.99). The rate of stroke in patients in the upper third of risk approximated to that in patients with AF (1.60 and 1.80 per 100 patient-years, respectively). Conclusions A small number of clinical variables identify a subset of patients with HF-PEF, but without AF, at elevated risk of stroke.
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| 215. |
- Abdul-Rahim, A. H., et al.
(författare)
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Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials
- 2015
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 131:17, s. 1486-94; discussion 1494
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF). METHODS AND RESULTS: We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by chi(2) value): age (hazard ratio, 1.34; 95% confidence interval, 1.18-1.63 per 10 years), New York Heart Association class (1.60, 1.21-2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22-2.88), body mass index (0.74, 0.60-0.91 per 5 kg/m(2) up to 30), and previous stroke (1.81, 1.19-2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11-1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF. CONCLUSIONS: A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.
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| 216. |
- Abdul-Sattar Aljabery, Firas, et al.
(författare)
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Management and outcome of muscle-invasive bladder cancer with clinical lymph node metastases. A nationwide population-based study in the bladder cancer data base Sweden (BladderBaSe)
- 2019
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Ingår i: Scandinavian journal of urology. - : Informa Healthcare. - 2168-1805 .- 2168-1813. ; 53:5, s. 332-338
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the clinical management and outcome of patients with muscle-invasive bladder cancer with clinical lymph node involvement, using longitudinal nationwide population-based data.Methods: In the Bladder Cancer Data Base Sweden (BladderBaSe), treatment and survival in patients with urinary bladder cancer clinical stage T2-T4 N + M0 diagnosed between 1997 and 2014 was investigated. Patients´ characteristics were studied in relation to TNM classification, curative or palliative treatment, cancer-specific (CSS) and overall survival (OS). Age at diagnosis was categorised as ≤60, 61-70, 71-80 and >80 years, and time periods were stratified as follows: 1997-2001, 2002-2005, 2006-2010 and 2011-2014.Results: There were 786 patients (72% males) with a median age of 71 years (interquartile range = 64-79 years). The proportion of patients with high comorbidity increased over time. Despite similar low comorbidity, curative treatment was given to 44% and to 70% of those in older (>70 years) and younger age groups, respectively. Curative treatment decreased over time, but chemotherapy and cystectomy increased to 25% during the last time period. Patients with curative treatment had better survival compared to those with palliative treatment, both regarding CSS and OS in the whole cohort and in all age groups.Conclusions: The low proportion of older patients undergoing treatment with curative intent, despite no or limited comorbidity, indicates missed chances of treatment with curative intent. The reasons for an overall decrease in curative treatment over time need to be analysed and the challenge of coping with an increasing proportion of node-positive patients with clinically significant comorbidity needs to be met.
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| 217. |
- Abdul-Sattar Aljabery, Firas, et al.
(författare)
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Treatment and prognosis of patients with urinary bladder cancer with other primary cancers: a nationwide population-based study in the Bladder Cancer Data Base Sweden (BladderBaSe)
- 2020
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Ingår i: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 126:5, s. 625-632
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Tidskriftsartikel (refereegranskat)abstract
- Objective To study how patients with urinary bladder cancer (UBC) with previous or concomitant other primary cancers (OPCs) were treated, and to investigate their prognosis. Patients And Methods Using nationwide population-based data in the Bladder Cancer Data Base Sweden (BladderBaSe), we analysed the probability of treatment with curative intent, and UBC-specific and overall survival (OS) in patients with UBC diagnosed in the period 1997-2014 with or without OPC. The analyses considered the patient's characteristics, UBC tumour stage at diagnosis, and site of OPC. Results There were 38 689 patients, of which 9804 (25%) had OPCs. Those with synchronous OPCs more often had T2 and T3 tumours and clinically distant disease at diagnosis than those with UBC only. Patients with synchronous prostate cancer, female genital cancer and lower gastro-intestinal cancer were more often treated with curative intent than patients with UBC only. When models of survival were adjusted for age at diagnosis, marital status, education, year of diagnosis, Charlson Comorbidity Index and T-stage, UBC-specific survival was similar to patients with UBC only, but OS was lower for patients with synchronous OPC, explained mainly by deaths in OPC primaries with a bad prognosis. Conclusions OPC is common in patients with UBC. Treatment for UBC, after or in conjunction with an OPC, should not be neglected and carries just as high a probability of success as treatment in patients with UBC only. The needs of patients with UBC and OPC, and optimisation of their treatment considering their complicated disease trajectory are important areas of research.
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| 218. |
- Abdula, Rahimaisa, 1976
(författare)
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Climate Change Policy of Bio-Energy: A Computable General Equilibrium Analysis
- 2005
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This paper explores the intersectoral and land-use dynamics behind bio-energyâ??s development as a climate change policy. Bio-energy from agriculture and forestry can potentially mitigate the emissions of carbon dioxide (CO2) from energy use and land-use changes (LUC) by its substitution to fossil fuels and its diversion of land-use to biomass plantation. Two major issues concerning its interplay with the other sectors of the economy and other land-use options are mapped in the study, namely its competition with other energy sources and sectors of similar production structure such as the crops and livestock sector; and its competition for land with other land-use based CO2 mitigation option of afforestation. By employing a computable general equilibrium with a land-use change model, the study was able to depict the various interfaces of bio-energy with the rest of the economy and with the land market. Moreover, the model enabled the mapping of policy implications upon the economy, welfare, and pattern of land-use changes and its subsequent contribution to CO2 emissions. The main policy considered in this study is the carbon taxation with revenues geared towards the reduction of direct taxes and towards the finance of bio-energy subsidy. Results showed that the carbon taxation per se does not ensure the growth of the bio-energy sector, unless the tax base is extended to land-use changes and unless the proceeds are directed to subsidize the sector or to buttress the incomes and consumptions of rural households; the main users of bio-energy. Investment in bio-energy as a complementary mitigation policy to carbon taxation has resulted into the improvements in the domestic capacity for energy sourcing and the welfare of the rural households. It successfully lowered the cost of mitigation by shifting reliance away from fossil fuels and by inducing land-use conversion to bio-energy and forestry purposes, without instigating dramatic transformations in the land-use system and without producing catastrophic burden upon the agricultural sector. Moreover, despite the competition for scarce land resource of the different land-use based mitigation options, synergies between developing carbon offset through bio-energy and building carbon sink through afforestation can be achieved through the market mechanism. The same benefits are presented by integrating land-use changes emissions into the carbon tax coverage.
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| 219. |
- Abdulkarim, Khadija
(författare)
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Population-Based Long-Term Follow-up of Patients with Myeloproliferative Neoplasms, complications and prognosis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABSTRACT Philadelphia chromosome negative myeloproliferative neoplasms (Ph-MPNs) are rare clonal hematological malignancies, mainly including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). Patients with these diseases run a high risk of vascular complications and may transform to acute myeloid leukemia (AML). Population-based studies relating to these issues are few in number. The aims were (i) to investigate the rate of AML development in subtypes of Ph-MPNs, (ii) to determine whether clinical and bone marrow findings at diagnosis have an impact on survival and vascular complications in PV and ET, (iii) to find prognostic tools based on clinical findings in newly diagnosed PV and (iv) to describe the “real”-life data from newly diagnosed PV and ET. We have investigated these issues in population-based material; study (i) and (iii) were based on patients from both Gothenburg, Sweden, and the Côte d`Or area, France. Study (ii) was based only from Gothenburg and study (iv) comprised PV and ET patients in the National MPN Registry. In the median observation period of 15 years, 7% (56 of 795) of patients with Ph-MPN transformed to AML. The yearly rate of AML transformation was significantly higher in MF (1.09%) compared with that of ET (0.37%) and PV (0.38%); (p = 0.02 and p = 0.002 respectively). Patients with PV had a significantly shorter survival compared with the general Swedish population (HR 1.66; CI: (1.38-1.99); p < 0.001). For ET, however, the corresponding survival differences did not reach statistical significance (HR 1.23; CI: (0.97-1.51); p = 0.089). Low hemoglobin at the time of diagnosis predicted poor survival in ET (p = 0.0281) and splenomegaly predicted poor survival in PV (p = 0.037). Using multivariate analysis, independent risk factors at diagnosis for survival in PV patients were identified as age > 70 years, WBC > 13×109/L and thrombotic events. Patients with none of these risk factors had a 10-year relative survival (RS) of 84%, compared with 59% and 26% in patients with one and two or three risk factors respectively. In the fourth study, we showed that vascular complications preceded an MPN diagnosis in 35% of ET and 37% of PV and multivariate analysis identified low hemoglobin as a risk factor for thromboembolic complications in PV (p = 0.012), while in ET age > 65 years, WBC > 12 × 109 /L and the presence of the JAK2 V617F mutation were independent risk factors (p = 0.0004, p = 0.0038 and p = 0.0016 respectively).
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| 220. |
- Abdulla, Afrah, 1975
(författare)
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Nyanlända vuxnas andraspråksinlärning - möjligheter och hinder
- 2022
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Ingår i: Möjligheter till lärande - Andraspråksdidaktik i ett kritiskt perspektiv. - : Liber. - 9789147146956
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Bokkapitel (refereegranskat)abstract
- I detta kapitel diskuterar jag några av de faktorer som kan påverka nyanlända vuxnas uppfattningar om Sverige och svenska samhället, och därigenom inverka på deras andraspråksinlärning och attityderna till denna. Det finns både strukturella och individuella förutsättningar för detta lärande, där min tolkning är att de strukturella förutsättningarna sätter ramarna för och villkorar lärandet.
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