188 research outputs found
Musculoskeletal manifestations of systemic sclerosis
No full textAbstract not availableKathleen B. Morrisroe, Mandana Nikpour, Susanna M. Proudma
Measures of disease status in systemic sclerosis: a systematic review
No full textAbstract not availableTien Tay, Nava Ferdowsi, Murray Baron, Wendy Stevens, Marie Hudson, Susanna M.Proudman, Mandana Nikpour, Damage Index Working Group of the Scleroderma Clinical Trials Consortiu
A Micromachined Angled Hall Magnetic Field Sensor Using Novel In-Cavity Patterning
No full textThis paper will present a novel technique used in the fabrication of a three-dimensional magnetic field vector sensor based on an angled Hall plate structure. This new sensor design relies on simultaneously detecting all magnetic field vector components using Hall plates that are imbedded into the silicon sidewalls of a bulk micromachined cavity. A shadow mask technique was developed for the in-cavity patterning necessary for doping and metalization. This mask is made from standard thin film layers deposited onto a previously `un-etched` silicon surface. Therefore, the patterned layers also served as the etch mask to expose the silicon for anisotropic etching. This paper will concentrate on how an angled Hall device (AHD) can be fabricated using this technique
Molecular pathogenesis of refractory anemia with ring sideroblasts (RARS) : role of the mitochondrial iron transporter gene ABCB7
No full textRefractory anemia with ring sideroblasts (RARS) is characterized by anemia, erythroid apoptosis, and mitochondrial ferritin (FTMT) accumulation. Granulocyte-colony-stimulating factor (G-CSF) inhibits some of these features in vitro and in vivo and can in combination with erythropoietin normalize hemoglobin levels. The focus for this thesis was to investigate ABCB7 gene expression levels and mutational status in CD34+ cells and erythroblasts from MDS patients in order to understand mechanisms underlying the pathogenesis of RARS as well as the anti-apoptotic effects of G-CSF. Furthermore, we wanted to test the hypothesis that ABCB7 is a key mediator of aberrant iron accumulation in acquired RARS.To dissect these mechanisms, the CD34+ compartment of RARS bone marrow, as well as erythroblasts derived from CD34+ cells in an erythroblast culture system were subjected to gene expression analysis (GEP). Erythroblasts were also analyzed after incubation with G-CSF. The mutational and DNA methylation status of ABCB7 and other key down-regulated genes was assessed. To study the ABCB7 role in aberrant iron accumulation in RARS erythroblasts, we modulated the expression of ABCB7 in several cellular systems.ABCB7 is not mutated in RARS. However, CD34+ ABCB7 expression level was significantly lower compared to other MDS subtypes. Furthermore, there was a significant inverse relation between ABCB7 expression and the percentage of ring sideroblasts. In contrast to normal bone marrow, ABCB7 expression decreased during erythroid differentiation of RARS CD34+ cells. Other down-regulated key genes included MFN2, STAT5B, FANCC and the negative apoptosis regulator MAP3K7. Neither ABCB7, nor other down-regulated key genes in RARS showed hypermethylation. Several genes involved in erythropoiesis were significantly over- expressed in RARS CD34+ cells but showed normal or decreased expression in differentiating erythroblasts. Deregulated pathways in RARS erythroblasts included apoptosis and mitochondrial function.Interestingly, the mitochondrial pathway including MFN2 was significantly modified by G-CSF, and several heat shock protein genes were up-regulated, as evidence of anti-apoptotic protection of erythropoiesis. However, G-CSF had no effect on the expression of iron-transport or erythropoiesis-associated genes.ABCB7 down-regulation led to marked up-regulation of FTMT in K562 cells, while inhibiting growth and erythroid differentiation. In normal bone marrow, ABCB7 silencing reduced erythroid colony growth, and induced erythroid apoptosis and a gene expression pattern similar to that observed in RARS day 7 erythroblasts. Importantly, down-regulation led to the accumulation of mitochondrial iron, in the form of FTMT. ABCB7 up-regulation potentiated erythroid differentiation in K562 cells, and restored erythroid colony growth and decreased FTMT expression level in RARS CD34+ BM cells. Mutations in the SF3B1gene, a core component of the RNA splicing machinery, were recently identified in a high proportion of patients with RARS. Of the nine RARS patients included in our study, 7 carried SF3B1 mutations. Interestingly, SF3B1 silencing resulted in down-regulation of ABCB7.Our findings support an essential role of ABCB7 in the phenotype of acquired RARS and suggest a relation between SF3B1 mutations and ABCB7 down-regulation that warrants further investigation.List of scientific papersI. Boultwood J, Pellagatti A, Nikpour M, Pushkaran B, Fidler C, Cattan H, Littlewood TJ, Malcovati L, Della Porta MG, Jädersten M, Killick S, Giagounidis A, Bowen D, Hellström Lindberg E, Cazzola M, and Wainscoat JS. “The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts”. PLoS One. 2008 Apr 9;3 (4):e1970. https://doi.org/10.1371/journal.pone.0001970 II. Nikpour M, Pellagatti A, Liu A, Karimi M, Malcovati L, Gogvadze V, Forsblom AM, Wainscoat JS, Cazzola M, Zhivotovsky B, Grandien, A, Boultwood J, and Hellström Lindberg E. “Gene expression profiling of erythroblasts from refractory anaemia with ring sideroblasts (RARS) and effects of G-CSF”. Br J Haematol. 2010 Jun; 149(6):844-54. https://doi.org/10.1111/j.1365-2141.2010.08174.x III. Nikpour M*, Liu A*,Scharenberg C, Conte S, Giai V, Fernandez-Mercado M, Papaemmanuil E, Högstrand K, Jansson M, Forsblom L, Vedin I, Sander B, Wainscoat JS, Campbell P, Cazzola M, Boultwood J, Grandien A, Hellström-Lindberg E. “The iron transporter gene ABCB7 is essential for the phenotype of acquired refractory anemia with ring sideroblasts”. *Equal contribution. [Manuscript]</p
Gene expression profiling of erythroblasts from refractory anaemia with ring sideroblasts (RARS) and effects of G-CSF.
No full textRefractory anaemia with ring sideroblasts (RARS) is characterized by anaemia, erythroid apoptosis, cytochrome c release and mitochondrial ferritin accumulation. Granulocyte-colony-stimulating factor (G-CSF) inhibits the first three of these features in vitro and in vivo. To dissect the molecular mechanisms underlying the RARS phenotype and anti-apoptotic effects of G-CSF, erythroblasts generated from normal (NBM) and RARS marrow CD34+ cells were cultured ±G-CSF and subjected to gene expression analysis (GEP). Several erythropoiesis-associated genes that were deregulated in RARS CD34+ cells showed normal expression in erythroblasts, underscoring the importance of differentiation-specific GEP. RARS erythroblasts showed a marked deregulation of several pathways including apoptosis, DNA damage repair, mitochondrial function and the JAK/Stat pathway. ABCB7, transporting iron from mitochondria to cytosol and associated with inherited ring sideroblast formation was severely suppressed and expression decreased with differentiation, while increasing in NBM cultures. The same pattern was observed for the mitochondrial integrity gene MFN2. Other downregulated key genes included STAT5B, HSPA5, FANCC and the negative apoptosis regulator MAP3K7. Methylation status of key downregulated genes was normal. The mitochondrial pathway including MFN2 was significantly modified by G-CSF, and several heat shock protein genes were upregulated, as evidence of anti-apoptotic protection of erythropoiesis. By contrast, G-CSF had no effect on iron-transport or erythropoiesis-associated genes
Finite element simulations and experimental investigations on ductile fracture in cold forging of aluminum alloy
No full textPredicting trajectories of lung function decline in systemic sclerosis–related interstitial lung disease
No full textObjective SSc-related interstitial lung disease (SSc-ILD) is a major cause of morbidity. We aimed to identify patients following similar trajectories of forced vital capacity (FVC) decline, and examine their association with mortality and risk factors for FVC decline. Methods This is a multicentre retrospective study of 444 SSc patients with ILD and ≤7-year disease duration. Patients were grouped based on similar FVC decline trajectories using semi-parametric modelling with latent class analysis. Survival was compared between the worst FVC trajectory group and the others. Logistic regression models with backwards selection were applied to identify predictors of FVC trajectory using baseline disease features. Results Four FVC trajectory groups were identified. The most progressive trajectory declined by –2.18% per year and the other three trajectory groups were stable or progressed slowly. The most progressive group had a higher mortality rate than those with a stable/slow FVC trajectory (hazard ratio 2.95, 95% CI 1.74, 4.98). Baseline FVC (P < 0.001) and CRP elevation (P = 0.039) were associated the progressive trajectory. Baseline FVC ≤72% predicted the progressive trajectory with a sensitivity of 0.88 and specificity of 0.91. A lower baseline FVC was in turn associated with older age, Caucasian race, longer disease duration, anti-topoisomerase I presence and elevated CRP on exploratory analyses. Conclusion Distinct FVC trajectories are associated with different survival outcomes and the most important predictor of a progressive FVC trajectory was existing ILD severity. More work is needed to assess the utility of imaging or paraclinical findings that can improve prediction of distinct FVC trajectories.Boyang Zheng, Mandana Nikpour, Wendy Stevens, Susanna Proudman, Kathleen Morrisroe, Mianbo Wang, Ada Man, Murray Baro
Identifying and Quantifying Dynamic Risk Factors for Coronary Artery Disease in Systemic Lupus Erythematosus
No full textSystemic Lupus Erythematosus (SLE), a prototypic multi-organ autoimmune disease, is associated with a dramatically increased risk of coronary artery disease (CAD) manifesting as angina, myocardial infarction and sudden cardiac death. Traditional cardiac risk factors such as hypertension and hypercholesterolemia, measured at baseline in accordance with the Framingham model, only partially account for the increased risk of CAD in SLE. In this thesis, I have shown that blood pressure (BP), lipids and novel risk factors such as the inflammatory marker high-sensitivity C-reactive protein (hsCRP), take a dynamic course in SLE, with more than half of the variance in serial measurements over time occurring within rather than between individuals. This variability is due to changes in disease activity, treatment, accrual of other cardiac risk factors, and complications such as infection. I have demonstrated that by capturing cumulative exposure over time, ‘summary measures’ such as arithmetic mean and time-adjusted mean (AM) are better able to quantify CAD risk in patients with SLE than single-point-in-time measurements of risk factors. By incorporating ‘summary measures’ such as mean and AM into time-dependent covariate survival analysis models, I was able to quantify the magnitude of increase in CAD risk associated with increments in systolic and diastolic BP, and to demonstrate and quantify the association between several lipids / lipoproteins and CAD risk in SLE. Using this methodology, I was also able to demonstrate that despite marked variability over time, ‘summary measures’ of hsCRP are independently predictive of CAD risk among patients with SLE, highlighting the pivotal role of inflammation in atherosclerosis. Furthermore, I was able to determine lipid and hsCRP ‘cut-points’ that will aid clinicians in identifying a subgroup of patients with SLE who are at significantly increased cardiac risk.Ph
Measurement of the performance of a radial inflow turbine
No full textSIGLEAvailable from British Library Document Supply Centre- DSC:D188709 / BLDSC - British Library Document Supply CentreGBUnited Kingdo
STUDY OF MORBIDITY AND MORTALITY OF CHILDREN UNDER 5 YEARS OF AGE IN BEHBAHAN CITY, IRAN
No full textIn a survey of the Population of Behbahan city, carried out in years 1990-91, the mean age was approximated up to 15.2 and 17.5 in the villages and the city, respectively. Furthermore, about 27.4% and 27.9% of the corresponding populations were under 5 years of age. The birth rate in the urban and rural areas was about 31.2 and 33.3 per thousand live births. Mortality rate related to the immaturity and low-birth weight were two times more in villages than in the city. There is a meaningful relationship between intent’s body weight and IMR in the villages but both in the city
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