985 resultados para Project 2003-026-C : 2003-026-C


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High systemic levels of IP-10 at onset of combination therapy for chronic hepatitis C mirror intrahepatic mRNA levels and predict a slower first phase decline in HCV RNA as well as poor outcome. Recently several genome wide association studies have revealed that single nucleotide polymorphisms (SNPs) on chromosome19 within proximity of IL28B predict spontaneous clearance of HCV infection and as therapeutic outcome among patients infected with HCV genotype 1, with three such SNPs being highly predictive: rs12979860, rs12980275, and rs8099917. In the present study, we correlated genetic variations in these SNPs from 253 Caucasian patients with pretreatment plasma levels of IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO). The favorable genetic variations in all three SNPs (CC, AA, and TT respectively) was significantly associated with lower baseline IP-10 (CC vs. CT/TT at rs12979860: median 189 vs. 258 pg/mL, P=0.02, AA vs. AG/GG at rs12980275: median 189 vs. 258 pg/mL, P=0.01, TT vs. TG/GG at rs8099917: median 224 vs. 288 pg/mL, P=0.04), were significantly less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P=0.01 respectively) and had significantly higher baseline viral load than carriers of the SNP genotypes (6.3 vs. 5.9 log 10 IU/mL, P=0.0012, 6.3 vs. 6.0 log 10 IU/mL, P=0.026, and 6.3 vs. 5.8 log 10 IU/mL, P=0.0003 respectively). Among HCV genotype 1 infected homozygous or heterogeneous carriers of the favorable C, A, and T genotypes, lower baseline IP-10 was significantly associated with greater decline in HCV-RNA day 0-4, which translated into increased rates of achieving SVR among homozygous patients with baseline IP-10 below 150 pg/mL (85%, 75%, and 75% respectively). In a multivariate analysis among genotype 1 infected patients, both baseline IP-10 and the SNPs were significant independent predictors of SVR. Conclusion: Baseline plasma IP-10 is significantly associated with IL28B variations, and augments the predictiveness of the first phase decline in HCV RNA and final treatment outcome.

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Résumé La dérégulation de c-Myc est un événement fréquent de la transformation cellulaire. Une régulation positive de cette oncoprotéine a été démontrée dans divers mélanomes cutanés primaires et métastatiques et est associée à un pronostic défavorable (Grover et al., 1996; Zhuang et al., 2008). c-Myc est considéré comme une molécule centrale impliquée dans plusieurs processus de l'homéostasie cellulaire. En raison de sa contribution importante dans la progression tumorale, la fonction de c-Myc a été étudiée intensément. Cependant nous connaissons peu le rôle de ce facteur de transcription dans l'embryogenèse et dans la spécification tissulaire. Un déficit total de c-Myc pendant l'embryogenèse conduit à la mort embryonnaire avant 10.5 jours de gestation. Cette mort est causée par de multiples imperfections du développement touchant la taille de l'embryon, le coeur, le péricarde, le tube neural et les cellules sanguines (Davis et al., 1993; Trumpp et al., 2001). Récemment, il a été montré que la plupart de ces anomalies sont secondaires et résultent d'une insuffisance du placenta dans les embryons c-myc-/- (Dubois et al., 2008). Sachant que c-Myc est important dans la maintenance des lignées de la crête neurale (Wei et al., 2007), nous nous sommes intéressés au rôle de c-Myc dans le développement des cellules pigmentaires et à leur homéostasie après la naissance. Un allèle floxé de c-myc (Trumpp et al., 2001) a été utilisé pour supprimer ce gène spécifiquement dans la lignée mélanocytaire à l'aide d'une souris transgénique Tyr::Cre (Delmas et al., 2003). L'ablation des deux allèles de c-myc dans les mélanocytes des souris c-myccKO conduit au phénotype de grisonnement des poils, observé directement après la naissance et associé à une diminution du nombre de mélanocytes dans le bulbe des follicules pileux. Les cellules pigmentaires restantes expriment les marqueurs mélanogéniques (Tyr, TRP-1, Dct and MITF) et semblent être fonctionnelles puisqu'elles peuvent produire et transférer la mélanine. De plus, la capacité de prolifération des mélanocytes déficients en c-Myc dans le bulbe des follicules pileux ne semble pas être affectée chez les nouveaux-nés. Les cellules souches mélanocytaires sont présentes, mais en nombre réduit, dans le bulge des follicules pileux à la fin de la morphogenèse chez les souris c-myccKO âgées de huit jours. Ces cellules sont maintenues sans changement durant le premier cycle pileux (vérifié à l'âge de trente jours), ce qui sous-entend que la fonction de c-Myc n'est pas nécessaire pour ce processus. Ceci explique pourquoi, en supposant que des cellules souches mélanocytaires fonctionnelles sont présentes dans la peau, nous n'observons pas de dilution de couleur de la robe liée à l'âge. Cependant, la présence de ces cellules souches mélanocytaires dans la peau c-myccKO ne suffit pas à assurer une quantité normale de mélanocytes différenciés dans le bulbe des follicules pileux. Cette population de cellules pigmentaires matures est sévèrement affectée par la suppression de c-Myc, ce qui contribue amplement au phénotype de grisonnement des poils. De plus, c-Myc paraît être important pour le développement des mélanocytes. Ainsi, le nombre de mélanoblastes diminue dans les embryons c-myccKO à partir du douzième jour de gestation. A treize jours de gestation, au stade où les mélanoblastes pénètrent dans l'épiderme et prolifèrent, les mélanoblastes déficients en c-Myc ne s'adaptent pas aux signaux de prolifération et se retrouvent en nombre réduit dans l'épiderme. Finalement, nous nous sommes intéressés, au rôle de N-Myc, un homologue proche de c-Myc, dans la lignée mélanocytaire. Nos expériences ont montré que. N-Myc était superflu pour le développement et l'homéostasie des mélanocytes, une seule copie du gène c-myc étant suffisante pour maintenir une pigmentation normale de la robe des souris c-mycc-myccKO/+~N_ myccKO/KO. Cependant, le rôle essentiel de N-Myc dans la maintenance des cellules mélanocytaires précurseurs apparaît lorsque c-Myc est absent, puisque la suppression simultanée des deux Myc résulte en une perte complète de la coloration de la robe. Ceci implique la présence d'un mécanisme compensatoire entre c- et N-Myc dans la lignée mélanocytaire, avec un rôle prédominant de c-Myc. Summary Deregulation of c-Myc is known to be a common event in cellular transformation. Upregulation of this oncoprotein was shown in a variety of primary and metastatic cutaneous melanomas and has been associated with a poor prognosis (Grover et al., 1996; Zhuang et al., 2008). c-myc is seen as a central molecule involved in many aspects of cellular homeostasis. c-Myc function has been intensively studied mostly because of its significant contribution to tumour progression. However little is known on the role of this transcription factor in embryogenesis and tissue specification. Complete loss of c-Myc during embryogenesis results in embryonic death before E10.5 due to multiple developmental defects including embryonic size, heart, pericardium, neural tube and blood cells (Davis et al., 1993; Trumpp et al., 2001). Recently it was discovered that most of these abnormalities are secondary and results of placental insufficiency in c-Myc-/- embryos (Dubois et al., 2008). Here, we focused on the role of c-Myc in pigment cell development and homeostasis after birth, knowing that c-Myc is important in the maintenance of neural crest lineages (Wei et al., 2007). A floxed allele of c-Myc (Trumpp et al., 2001) was used to specifically delete this gene in the melanocyte lineage using Tyr::Cre transgenic mice (Delmas et al., 2003). Removal of both c-Myc alleles in melanocytes of c-MyccKO mouse led to the grey hair phenotype which is seen directly after birth and was associated with a decrease in the melanocyte number in the bulb of the hair follicle. The remaining population of pigment cells express melanogenic markers (Tyr, TRP-1, Dct and MITF) and seem functionally normal since they can produce and transfer melanin. Furthermore proliferation capacity of c-Myc deficient melanocytes in the bulb of hair follicle seems not to be affected in newborn animals. Melanocyte stem cells (MSCs) are present but reduced in numbers in the bulge of the hair follicle at the end of morphogenesis in 8 days old c-MyccKO mice. These cells are maintained through the first hair cycle (as verified at P30) without any further changes, suggesting that c-Myc function is not required for this process. This explains why we did not detect any agerelated coat color dilution, assuming a presence of functional MSCs in the skin. Importantly, presence of MSCs in c-MyccKO skin was not sufficient for assuring a normal number of differentiated melanocytes in the bulb of the hair follicle. This population of mature pigmented cells is severely affected upon c-myc deletion thus largely contributing to the grey hair phenotype. Moreover, c-Myc appears to be important for melanocyte development. Thus, melanoblast number is affected in c-MyccKO embryos day 12 of gestation onwards. At E13.5, when melanoblasts enter the epidermis and proliferate, c-myc deficient melanoblasts failed to adapt to proliferation signals and are therefore reduced in number in the epidermis. Finally, we addressed the role of N-Myc, a closest homologue of c-Myc, in the melanocyte lineage. In these experiments, N-Myc was dispensable for melanocyte development and homeostasis, and even one copy of the c-myc gene was sufficient to maintain normal coat color pigmentation in c-mycc-mycCKO/+ ,N-myccKO/KO mice. However the crucial role of N-Myc in maintenance of melanocyte precursor cells became apparent when c-myc is eliminated since simultaneous deletion of both Myc results in complete loss of coat color pigmentation. This suggests compensatory mechanisms between c- and N-Myc with a predominant role of c-Myc in melanocyte lineage.

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The use of Railroad Flatcars (RRFCs) as the superstructure on low-volume county bridges has been investigated in a research project conducted by the Bridge Engineering Center at Iowa State University. These bridges enable county engineers to replace old, inadequate county bridge superstructures for less than half the cost and in a shorter construction time than required for a conventional bridge. To illustrate their constructability, adequacy, and economy, two RRFC demonstration bridges were designed, constructed, and tested: one in Buchanan County and the other in Winnebago County. The Buchanan County Bridge was constructed as a single span with 56-ft-long flatcars supported at their ends by new, concrete abutments. The use of concrete in the substructure allowed for an integral abutment at one end of the bridge with an expansion joint at the other end. Reinforced concrete beams (serving as longitudinal connections between the three adjacent flatcars) were installed to distribute live loads among the RRFCs. Guardrails and an asphalt milling driving surface completed the bridge. The Winnebago County Bridge was constructed using 89-ft-long flatcars. Preliminary calculations determined that they were not adequate to span 89 ft as a simple span. Therefore, the flatcars were supported by new, steel-capped piers and abutments at the RRFCs' bolsters and ends, resulting in a 66-ft main span and two 10-ft end spans. Due to the RRFC geometry, the longitudinal connections between adjacent RRFCs were inadequate to support significant loads; therefore, transverse, recycled timber planks were utilized to effectively distribute live loads to all three RRFCs. A gravel driving surface was placed on top of the timber planks, and a guardrail system was installed to complete the bridge. Bridge behavior predicted by grillage models for each bridge was validated by strain and deflection data from field tests; it was found that the engineered RRFC bridges have live load stresses significantly below the AASHTO Bridge Design Specification limits. To assist in future RRFC bridge projects, RRFC selection criteria were established for visual inspection and selection of structurally adequate RRFCs. In addition, design recommendations have been developed to simplify live load distribution calculations for the design of the bridges. Based on the results of this research, it has been determined that through proper RRFC selection, construction, and engineering, RRFC bridges are a viable, economic replacement system for low-volume road bridges.

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Our goal was to evaluate the diagnostic utility of C-reactive protein (CRP) alone or combined with clinical probability assessment in patients with suspected pulmonary embolism (PE), and to compare its performance to a D-dimer assay. We conducted a prospective study in which we performed a common immuno-turbidimetric CRP test and a rapid enzyme-linked immunosorbent assay (ELISA) D-dimer test in 259 consecutive outpatients with suspected PE at the emergency department of a teaching hospital. We assessed clinical probability of PE by a validated prediction rule overridden by clinical judgment. Patients with D-dimer levels &gt; or = 500 microg/l underwent a work-up consisting of lower-limb venous ultrasound, spiral computerized tomography, ventilation-perfusion scan, or pulmonary angiography. Patients were followed up for three months. Seventy-seven (30%) of the patients had PE. The CRP alone had a sensitivity of 84% (95% confidence interval [CI).: 74 to 92%) and a negative predictive value (NPV) of 87% (95% CI: 78 to 93%) at a cutpoint of 5 mg/l. Overall, 61 (24%) patients with a low clinical probability of PE had a CRP &lt; 5 mg/l. Due to the low prevalence of PE (9%) in this subgroup, the NPV increased to 97% (95% CI: 89 to 100%). The D-dimer (cutpoint 500 micro g/l) showed a sensitivity of 100% (95% CI: 95 to 100%) and a NPV of 100% (95% CI: 94 to 100%) irrespective of clinical probability and accurately rule out PE in 56 (22%) patients. Standard CRP tests alone or combined with clinical probability assessment cannot safely exclude PE.

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The Mississippi River Trail (MRT) is a world-class bicycle trail that will follow the Mississippi River all the way from its headwaters in Minnesota to the Gulf of Mexico. The trail is partially completed; much of it is still in the planning and development stages. When complete, the MRT will Link over 2,000 miles of recreational trails through 10 states, including 280 miles in Iowa. Designated as a National Millennium Trail, the MRT will preserve natural environments along the river, stimulate economic growth in river communities, and provide bicyclists access to a variety of landscapes, history, and culture. The Iowa Department of Transportation commissioned the Center for Transportation Research and Education at Iowa State University to develop a plan for a safe, economically beneficial, and scenic MRT route through Iowa. This report presents the MRT plan for Iowa. It is organized in the following chapters: Executive Summary; (1) Introduction - vision statement and objectives; (2) Iowa MRT Minimum Design Standards; (3) Iowa MRT Route Analysis; (4) Recommended Improvement Plan; (5) MRT Implementation; and (6) Estimated Benefits and Impacts of the Iowa MRT. Additional information is provided in the following appendices: (A) GIS Analysis for the MRT; (B) Iowa MRT Maps; (C) Public Input; (D) Public Comments; and (E) References.

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In vertebrates, different isoforms of fibroblast growth factor 2 (FGF2) exist, which differ by their N-terminal extension. They show different localization and expression levels and exert distinct biological effects. Nevertheless, genetic inactivation of all FGF2 isoforms in the mouse results in only mild phenotypes. Here, we analyzed mouse FGF2, and show that, as in the human, mouse FGF2 contains CTG-initiated high molecular-weight (HMW) isoforms, which contain a nuclear localization signal, and which mediate localization of this isoform to the nucleus. Using green fluorescent protein-FGF2 fusions, we furthermore observed, that C-terminal deletions disable nuclear localization of the short low-molecular-weight (LMW) 18-kDa isoform. This loss of specific localization is accompanied by a loss in heparin binding. We therefore suggest that, first, localization of mouse FGF2 is comparable to that in other vertebrates and, second, FGF2 contains at least two sequences important for nuclear localization, a nuclear localization sequence at the N terminus which is only contained in the HMW isoform, and another sequence at the C terminus, which is only required for localization of the LMW 18-kDa isoform.

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The world-class Idrija mercury deposit (western Slovenia) is hosted by highly deformed Permocarboniferous to Middle Triassic sedimentary rocks within a complex tectonic structure at the transition between the External Dinarides and the Southern Alps. Concordant and discordant mineralization formed concomitant with Middle Triassic bimodal volcanism in an aborted rift. A multiple isotopic (C, O, S) investigation of host rocks and ore minerals was performed to put constraints on the source and composition of the fluid, and the hydrothermal alteration. The distributions of the delta(13)C and delta(18)O values of host and gangue carbonates are indicative of a fracture-controlled hydrothermal system, with locally high fluid-rock ratios. Quantitative modeling of the delta(13)C and delta(18)O covariation for host carbonates during temperature dependent fluid-rock interaction, and concomitant precipitation of void-filling dolomites points to a slightly acidic hydrothermal fluid (delta(13)Capproximate to-4parts per thousand and delta(18)Oapproximate to+10parts per thousand), which most likely evolved during isotopic exchange with carbonates under low fluid/rock ratios. The delta(34)S values of hydrothermal and sedimentary sulfur minerals were used to re-evaluate the previously proposed magmatic and evaporitic sulfur sources for the mineralization, and to assess the importance of other possible sulfur sources such as the contemporaneous seawater sulfate, sedimentary pyrite, and organic sulfur compounds. The delta(34)S values of the sulfides show a large variation at deposit down to hand-specimen scale. They range for cinnabar and pyrite from -19.1 to +22.8parts per thousand, and from -22.4 to +59.6parts per thousand, respectively, suggesting mixing of sulfur from different sources. The peak of delta(34)S values of cinnabar and pyrite close to 0parts per thousand is compatible with ore sulfur derived dominantly from a magmatic fluid and/or from hydrothermal leaching of basement rocks. The similar stratigraphic trends of the delta(34)S values of both cinnabar and pyrite suggest a minor contribution of sedimentary sulfur (pyrite and organic sulfur) to the ore formation. Some of the positive delta(34)S values are probably derived from thermochemical reduction of evaporitic and contemporaneous seawater sulfates.

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Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins, that principally effect the viability of sensory hair cells via the MAP kinase (MAPK) cell death signaling pathway that incorporates c-Jun N-terminal kinase (JNK). We evaluated the otoprotective efficacy of D-JNKI-1, a cell permeable peptide that blocks the MAPK-JNK signal pathway. The experimental studies included organ cultures of neonatal mouse cochlea exposed to an ototoxic drug and cochleae of adult guinea pigs that were exposed to either an ototoxic drug or acoustic trauma. Results obtained from the organ of Corti explants demonstrated that the MAPK-JNK signal pathway is associated with injury and that blocking of this signal pathway prevented apoptosis in areas of aminoglycoside damage. Treatment of the neomycin-exposed organ of Corti explants with D-JNKI-1 completely prevented hair cell death initiated by this ototoxin. Results from in vivo studies showed that direct application of D-JNKI-1 into the scala tympani of the guinea pig cochlea prevented nearly all hair cell death and permanent hearing loss induced by neomycin ototoxicity. Local delivery of D-JNKI-1 also prevented acoustic trauma-induced permanent hearing loss in a dose-dependent manner. These results indicate that the MAPK-JNK signal pathway is involved in both ototoxicity and acoustic trauma-induced hair cell loss and permanent hearing loss. Blocking this signal pathway with D-JNKI-1 is of potential therapeutic value for long-term protection of both the morphological integrity and physiological function of the organ of Corti during times of oxidative stress.

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Tämä opetusmoniste koostuu turbokonetekniikan seminaarin lukuvuonna 2002-2003 suorittaneiden perus- ja jatko-opiskelijoiden laatimista seminaariesitelmistä. Opetusmoniste koostuu seuraavista osista: Jani Ikonen: Materiaalin valinta kaasuturbiinin turbiiniin huomioiden uusimmat materiaalit. 20 sivua. Ikonen esittää työssään katsauksen materiaalien valintaan kaasuturbiinissa, korkean lämpötilan materiaalien tulevaisuudennäkymiin,korroosiolta ja korkeilta lämpötiloilta suojaaviin pinnoitteisiin sekä joihinkin teollisuuskaasuturbiinien komponenttien valmistusmenetelmiin. Jouni Ritvanen: Värähtelymittaukset ja niiden tulkinta. 19 sivua. Kaikki laitteet värähtelevät käydessään. Värähtelyä aiheutuu yleensä epätasapainosta, valmistus- tai asennusvirheistä sekä kuluneista tai muuten vaurioituneista osista. Ritvanen tarkastelee työssään värähtelyä, värähtelyn mittausta ja tuloksien tarkastelua. Jarkko Vanhanen: Vaaka-akselisen 3 MW:n tuuliturbiinin siipien perussuunnittelu Utön olosuhteisiin, 18 sivua Vanhanen mitoittaa työssään 3 MW:n tuulivoimalan Utön ulkosaariston olosuhteisiin. Tuuliturbiini on vaaka-akselinen ja 3 siipinen. Mitoituksessa käytetään Schmitzin menetelmää joka on tarkempi kuin Betzin kriteeri. Weibull-jakauman avulla lasketaan mitoituksella saadun turbiinin teho eri kuukausina. Lisäksi tarkastellaan huipun käyttöaikaa ja tuotettua energiamäärää. Jani Keränen:Kolmidimesionaalinen siipisolavirtaus aksiaaliturbiinissa. 12 sivua. Keränen käsittelee työssään kolmidimensionaalista virtausta aksiaalisessa turbokoneessa. Työssä luodaan kuva toisiovirtauksen pääkomponentteihin: hevosenkenkäpyörteeseen,kanavapyörteeseen, kulmapyörteisiin ja jättöreunapyörteisin. Työssä selitetään kyseisten pyörteiden aiheuttamien häviöiden alkuperää ja tuodaan esille joitain keinoja, joilla pyörteilyä hallitaan. Lisäksi aihetta on käsitelty suppeasti myös numeerisen virtauslaskennan (CFD:n) kannalta. Teemu Turunen-Saaresti: Radiaalikompressorin ajansuhteen tarkka CFD-laskenta. 15 sivua. Turunen-Saaresti on seminaarityössään laskenut ajansuhteen tarkalla CFD-laskennalla radiaalikompressorinkahdessa eri toimintapisteessä. Lasketut toimintapisteet ovat suunnittelupiste ja toimintapiste lähellä tukkeumaa. Ajansuhteen tarkassa laskennassa mallinnetaan koko kompressori ja kytketään pyörivät ja paikallaan olevat osat toisiinsa liukuhilatekniikan avulla. Laskettuja arvoja verrataan Virtaustekniikan laboratoriossa kyseisestä kompressorista tehtyihin mittaustuloksiin.

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Cardiac failure is one of the leading causes of mortality in developed countries. As life expectancies of the populations of these countries grow, the number of patients suffering from cardiac insufficiency also increase. Effective treatments including the use of calcium sensitisers are being sought. They cause a positive inodilatory effect on cardio-myocytes without deleterious effects (arrhythmias) resulting from increases in intracellular calcium concentration. Levosimendan is a novel calcium sensitiser that hasbeen proved to be a welltolerated and effective treatment for patients with severe decompensated heart failure. Cardiac troponin C (cTnC) is its target protein. However, there have been controversies about the interactions between levosimendan and cTnC. Some of these controversies have been addressed in this dissertation. Furthermore, studies on the calcium sensitising mechanism based on the interactions between levosimendan and cTnC as followed by nuclear magnetic resonance(NMR) are presented and discussed. Levosimendan was found to interact with bothdomains of the calcium-saturated cTnC in the absence of cardiac troponin I (cTnI). In the presence of cTnI, the C-domain binding site was blocked and levosimendan interacted only with the regulatory domain of cTnC. This interaction may have caused the observed calcium sensitising effect by priming the N-domain for cTnI binding thereby extending the lifetime of that complex. It is suggested that this is achieved by shifting the equilibrium between open and closed conformations.

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Se presentan diversas cuestiones de la relación entre los modelos helénicos de las colonias de Emporion y Rhode y las costumbres indígenas evidenciadas en los yacimientos ibéricos de su entorno. Los cultos de Artemis y Apolo como dioses protectores de la emporía arcaica de los foceos, el urbanismo de Rhode en el siglo III a.C., los cultos emporitanos, la interpretación del yacimiento de Pontós, la mezcla de cultos griegos y celtas en Ullastret y Pontós y un cálato excepcional en un campo de silos al pie de S. Julià, se estudian como evidencias de esta relación. En el siglo II a.C., Roma implantará un nuevo orden político y económico del que Emporion será la gran beneficiada.

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Aquesta guia és una introducció a la creació de documents digitals accessibles amb el processador de textos Microsoft Word 2003.

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Aquesta guia és una introducció a la creació de presentacions digitals accessibles amb Microsoft PowerPoint 2003.