The purpose of this work is to measure the degree of intelligibility of native and non-native English speech as well as analyse the major sources of intelligibility failure when speakers of these varieties of English interact. British and American English (henceforth BrE and AmE) and Cameroon English (hereafter CamE) are used as a case study with focus on segmental and supra segmental features. The study was motivated by a number of concerns, several of which are more prominent: First, it was motivated by the trepidation scholars like Gimson (1965, 1980); Prator (1968); etc. nursed that the unprecedented spread of English across the globe and the emergence of non-native varieties would cause English to disintegrate into mutually unintelligible languages, in the way Romance languages devolved from their Latin ancestor. The second motivation was that previous researchers (Bansal 1969, Tiffen 1974) on intelligibility have often concentrated their efforts on the traditional approach, which sees intelligibility from a one-sided perspective. To them, the non-native varieties of English are deficient and not different varieties from the native varieties. They were seen as substandard, incorrect, and unintelligible and thus needed remediation at all costs. The native varieties were seen as prestigious, correct, intelligible and the sole norm that must be emulated by non-native English speakers. In this way any interaction between a native speaker and a non-native speaker should be characterised by the non-native speaker making all the efforts to be understood as well as to understand the native English-speaking partner. This explains in large part why these researchers concentrated on measuring the intelligibility of non-native speech to native speakers and never vice versa. It was as if it was treasonable to measure the intelligibility of native speech to non-native speakers. Even if some researchers managed to do this, the comments that followed such data still showed that the aim was not to test the intelligibility of native speakers but to find out how efficient the non-native speakers were in understanding the native speaker. Another aim could also be to reinforce the teaching of the native norm, which was seen as “correct” against non-native features, which were seen as “incorrect”, to measuring intelligibility. While accepting that these studies reflected the conventional wisdom of the time, this study aims to move the debate forward by looking at intelligibility from a two-sided perspective. It sees communication between speakers of different varieties as a game of give and take, where both participants “tune in” to make the process successful rather than one participant being obliged to make all the efforts because s/he speaks a new English variety. That explains why we are testing not only the intelligibility of non-native speakers to native speakers but also native speakers to non-native speakers. / Gegenstand der vorgelegten Promotionsarbeit ist die Untersuchung der gegenseitigen Verständlichkeit von muttersprachlichem und nicht-muttersprachlichem Englisch. Im besonderen werden die Hauptquellen und Ursachen des Scheiterns von Verständlichkeit in einer empirischen Studie bestimmt, klassifiziert und analysiert. Die Untersuchung wird exemplarisch anhand des Kamerunischen Englisch einerseits und des Britischen und Amerikanischen Englisch anderseits vorgenommen. Motiviert ist diese Arbeit vor allem durch folgende Punkte. Erstens bedarf es der Auseinandersetzung mit den durch eine Reihe von Autoren geäußerten Befürchtungen (z.B. Gimson 1965, 1980 und Prator 1968), daß die Herausbildung und Entwicklung neuer Varianten des Englischen letztlich zu einer Auflösung des Englischen in gegenseitig nicht mehr verständliche Sprachen führt, ein Prozeß, wie er sich historisch bei der Entstehung der romanischen Sprachen aus dem Lateinischen vollzog. Derartige Befürchtungen werden genährt durch die bisher ohnegleichen fortschreitende Verbreitung des Englischen über den gesamten Globus. Hier ergibt sich die dringende Notwendigkeit vergleichender Studien zur gegenseitigen Verständlichkeit zwischen den bestehenden Varianten. Zweitens folgen die meisten zu diesem Thema vorliegenden Untersuchungen im wesentlichen einer traditionellen, überkommenen Grundperspektive: die nicht-muttersprachlichen Varianten des Englischen werden als „abweichend“ bzw. sogar „defizitär“ aus Sicht der muttersprachlichen betrachtet, nicht aber als eigenständige Sprachformen (z.B. Bansal 1969; Tiffen 1974). Dies führt nach Auffassung des Autors zu einer einseitigen Betrachtung und Bewertung. Im besonderen wird in der sprachlichen Interaktion bei einem solchen Zugang die Last zu verstehen und für den Kommunikationspartner verständlich zu sein einseitig dem nicht-muttersprachlichen Sprecher übertragen. Auf diesem Hintergrund untersuchen die vorliegenden Studien anderer Autoren primär die Verständlichkeit nicht-muttersprachlicher Sprachformen für den muttersprachlichen Sprecher, nicht jedoch die umgekehrte Konstellation. Wenn die umgekehrte Perspektive überhaupt berücksichtigt wird, so zeigen die Kommentare, daß nicht die Verständlichkeit muttersprachlicher Sprecher für den Nichtmuttersprachler eigentliches Ziel und Gegenstand der Untersuchung war, sondern vielmehr die Frage, wie effizient sich Nichtmuttersprachler beim Verstehen muttersprachlicher Äußerungen zeigten. Des weiteren stehen diese Studien oft im Kontext des Bestrebens, im institutionalisierten Spracherwerb die muttersprachlichen Normen gegen die nicht-muttersprachlichen Merkmale durchzusetzen, die als „nicht korrekt“ angesehen werden. Diese Positionen, der zugrundeliegende Zugang und die einseitige Ausrichtung bedürfen einer kritischen Auseinandersetzung.

Duplications and deletions are a major source of genomic variation. Duplications, specifically, have a significant impact on gene genesis and dosage, and the malaria parasite P. falciparum has developed resistance to a growing number of anti-malarial drugs via gene duplication. It also contains highly duplicated families of antigenically variable allelic genes. While specific genes and families have been studied, a comprehensive analysis of duplications and deletions within the reference genome and population has not been performed. We analyzed the extent of segmental duplications (SD) in the reference genome for P. falciparum, primarily by a whole genome self alignment. We discovered that while 5% of the genome identified as SD, the distribution within the genome was partition clustered, with the vast majority localized to the subtelomeres. Within the SDs, we found an overrepresentation of genes encoding antigenically diverse proteins exposed to the extracellular membrane, specifically the var, rifin, and stevor gene families. To examine variation of duplications and deletions within the parasite populations, we designed a novel computational methodology to identify copy number variants (CNVs) from high throughput sequencing, using a read depth based approach refined with discordant read pairs. After validating the program against in vitro lab cultures, we analyzed isolates from Senegal for initial tests into clinical isolates. We then expanded our search to a global sample of 610 strains from Africa and South East Asia, identifying 68 CNV regions. Geographically, genic CNV were found on average in less than 10% of the population, indicating that CNV are rare. However, CNVs at high frequency were almost exclusively duplications associated with known drug resistant CNVs. We also identified the novel biallelic duplication of the crt gene – containing both the chloroquine resistant and sensitive allele. The synthesis of our SD and CNV analysis indicates a CNV conservative P. falciparum genome except where drug and human immune pressure select for gene duplication.

INTRODUÇÃO: A Glomerulosclerose Segmentar e Focal (GESF) é a glomerulopatia primária mais prevalente no Brasil e sua incidência vem aumentando no mundo inteiro. Na sua forma primária, caracteriza-se clinicamente por acometer pessoas jovens e causar proteinúria acentuada, geralmente acompanhada de síndrome nefrótica. O mecanismo patogênico tem como evento principal a lesão ao podócito, desencadeado por fatores de natureza variada: vírus, drogas/medicamentos, imunológicos, etc. Em 2004, foi publicada a classificação de Columbia, propondo 5 variantes morfológicas distintas na GESF: colapsante (COL), usual (NOS), apical ou tip lesion (TIP), perihilar (PHI) e variante celular (CEL). Diversos estudos comprovam alterações moleculares em podócitos na GESF. Essas alterações são observadas em diversos sítios podocitários: em moléculas envolvidas na fenda de filtração (slit diaphragm), por exemplo, nefrina, podocina e CD2AP; em moléculas do citoesqueleto podocitário, como a -actinina-4 e sinaptopodina; em moléculas marcadoras de diferenciação dos podócitos, como CD10 e WT-1; e ainda em marcadores de divisão celular como Ki-67 e PCNA. Os objetivos desse estudo foram: 1-) classificar as lesões morfológicas de GESF em biópsia renais nas 5 variantes da GESF propostas na Classificação de Columbia; e 2-) analisar a ocorrência de alterações moleculares podocitárias nestes casos. MÉTODOS: Foram selecionados 131 casos de biópsias renais com diagnóstico de GESF primária no período de 1996 a 2006. Os casos foram classificados de acordo com os critérios de Columbia e posteriormente submetidos a reações imuno-histoquímicas para os marcadores CD10, WT-1, vimentina, sinaptopodina, -actinina-4, GLEPP-1, citoqueratina 8/18, citoqueratina 19 e Ki-67. Os resultados foram submetidos à análise estatística através do teste qui-quadrado. RESULTADOS: A classificação das variantes da GESF se distribuiu da seguinte forma: 38,2% de variante NOS, 36,6% de variante COL, 14,5% de variante TIP, 6,9% de variante PHI e 3,8% de variante CEL. Os casos da variante COL se destacaram das demais variantes pela perda de expressão de marcadores de diferenciação celular, como o CD10 e o WT-1 (p<0,01), perda da molécula do citoesqueleto -actinina-4 (p<0,01) e neo-expressão de citoqueratinas 8-18 (p<0,05) e 19 (p<0,01). Adicionalmente, os casos das variantes COL e CEL se destacam das outras variantes pela expressão do marcador de divisão celular Ki-67 (p<0,05). CONCLUSÃO: a variante COL destacou-se das demais em relação às alterações moleculares observadas na análise imuno-histoquímica. O diagnóstico diferencial desta forma de GESF tem importância clínica por ela estar associada a pior evolução e prognóstico em relação às demais variantes. A integração destes marcadores na rotina diagnóstica pode auxiliar no diagnóstico diferencial da GESF COL / INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) is the most prevalent primary glomerulopathy in Brazil and its incidence is increasing worldwide. Primary FSGS is characterized clinically by affecting young people and causing severe proteinuria, often accompanied by nephrotic syndrome. The pathogenesis is related to podocyte injury, which may be due to several factors: viruses, drugs, immunological, etc. In 2004, the Columbia classification of FSGS identified five histological variants of the disease: collapsing (COL), usual (NOS), tip lesion (TIP), perihilar (PHI) and cellular variant (CEL). Several studies have demonstrated molecular changes in podocytes of FSGS patients, which were observed in molecules involved in the filtering function of these cells (nephrin, podocina and CD2AP), in podocyte cytoskeleton molecules (-actinin-4, and synaptopodin), as well as in molecular markers of podocyte differentiation (CD10 and WT-1) and of cell division (Ki-67 and PCNA). The aim of this study was to classify the FSGS biopsies according to the Columbia classification and to analyze the occurrence of molecular changes in the five morphological variants. METHODS: 131 cases of renal biopsies with a diagnosis of primary FSGS in the period 1996 to 2006 were classified according to the criteria of Columbia and then submitted to immunohistochemical reactions with the following antibodies: CD10, WT-1, Vimentin, Synaptopodin, -actinin-4, GLEPP-1, cytokeratin 8-18, cytokeratin 19, and Ki-67. RESULTS: FSGS cases were classified into five variants as follows: 38.2% of NOS variant, 36.6% COL, 14.5% TIP, 6.9% PHI and 3.8% CEL. The COL variant cases distinguished themselves among the other for having lost the expression of CD10 and WT-1 (p <0.01), and also of -actinin-4 (p <0, 01). Furthermore, they gained expression of the cytokeratin 8-18 (p <0.05) and 19 (p <0.01). The group of CEL and COL variants together differed from the other variants regarding the expression of cell division marker Ki-67 (p <0.05). CONCLUSION: COL variant of FSGS presents molecular changes that differs from others and can be demonstrated by immunohistochemistry. The differential diagnosis of this variant is important because of the worse clinical outcome and prognosis it presents in comparison with other variants. The identification of these markers by immunohistochemical on the routine practice may be useful in the diagnosis of COL FSGS

L’implication d’un facteur circulant et des dysfonctions du système immunitaire entrainant les altérations de la barrière de filtration glomérulaire a été suggérée dans la pathogénèse de la hyalinose segmentaire et focal récidivante. Nous avons identifié par spectrométrie de masse la présence de la protéine CASK dans des sérums de patients après immunoadsoroption sur une colonne de protéine A. CASK recombinante est capable d'induire des modifications de l’architecture des podocytes in vitro, tels qu’une redistribution de la protéine de diaphragme de fente ZO-1 et de la protéine régulatrice d’actine synaptopodine, et une perte de fibres de stress d’actine. Ces podocytes acquièrent ainsi un phénotype motile et une perméabilité accrue à l’albumine en présence de CASK recombinante in vitro. L’injection de CASK chez des souris entraine une protéinurie et l’effacement des pédicelles de podocytes. L’interaction entre CASK et son récepteur CD98 dans les podocytes a été mise en évidence par l’expérience de pontage covalent et co-immunoprécipitation. L’inhibition de l’expression de CD98 par ARNi a permis de préserver l’architecture des podocytes en présence de CASK. Nous avons remarqué la surexpression de CASK dans les monocytes chez les patients atteints de la HSF récidivante par rapport aux témoins. In vitro, CASK est surexprimée dans les macrophages ayant une polarité M2 et est retrouvée dans le surnageant de la culture de ces cellules. La sécrétion de CASK est associée aux exosomes qui sont des microvésicules d’origine endosomale. Dans les cellules, CASK est partiellement co-distribuée avec ALIX, un marqueur exosomal, et leur interaction a été mise en évidence par co-immunoprécipitation. CASK est fortement exprimée dans les exosomes de patients atteints de HSF récidivante comparé aux donneurs sains. Le traitement des podocytes par des exosomes issus des macrophages de type M2 induit des altérations du cytosquelette et augmente la motilité des podocytes comme cela avait été observé en présence de CASK recombinante. Pour conclure, nous avons identifié CASK comme nouveau facteur soluble qui pourrait jouer un rôle au cours de la HSF récidivante après transplantation rénale. Ces découvertes ouvrent de nouvelles orientations pour le traitement des malades atteints de SNI récidivant. / Focal segmental glomerulosclerosis (FSGS) is often associated with a high rate of progression to end-stage renal disease. The idiopathic form has a high recurrence rate (rFSGS) after transplantation suggesting the presence of a systemic circulating factor that causes the glomerular permeability. This factor can be removed by plasmapheresis or immunoadsorption using protein-A columns. We used mass spectrometry to analyze the proteins eluted from protein-A columns, taken from patients with rFSGS after immunoadsorption. A serum form of calcium/calmodulin-dependent serine/threonine kinase (CASK) was identified in rFSGS patients but not in controls. In cultured podocytes, recombinant CASK induced reorganization of the actin cytoskeleton. We also demonstrated the interaction of CASK with CD98 at the cell surface. Injection of recombinant CASK in mice induced proteinuria and foot process effacement on podocytes. We identified that CASK is produced by monocytes in patients with rFSGS. CASK is also expressed and secreted by M2 polarized macrophages but not by M1 subset. CASK was associated with exosomes produced by these cells. CASK has a partial codistribution with ALIX, an exosomal component involved in their development. We’ve also demonstrated that CASK interacts with ALIX in M2 macrophages. Moreover exosomes derived from M2 macrophages cause podocytes cytoskeleton alterations and increase of podocyte motility as observed previously with recombinant CASK. In conclusion, a serum form of CASK secreted by macrophages acts as a permeability factor in patients with rFSGS suggesting its involvement in the physiopathology of rFSGS.

INTRODUÇÃO: A Glomerulosclerose Segmentar e Focal (GESF) é a glomerulopatia primária mais prevalente no Brasil e sua incidência vem aumentando no mundo inteiro. Na sua forma primária, caracteriza-se clinicamente por acometer pessoas jovens e causar proteinúria acentuada, geralmente acompanhada de síndrome nefrótica. O mecanismo patogênico tem como evento principal a lesão ao podócito, desencadeado por fatores de natureza variada: vírus, drogas/medicamentos, imunológicos, etc. Em 2004, foi publicada a classificação de Columbia, propondo 5 variantes morfológicas distintas na GESF: colapsante (COL), usual (NOS), apical ou tip lesion (TIP), perihilar (PHI) e variante celular (CEL). Diversos estudos comprovam alterações moleculares em podócitos na GESF. Essas alterações são observadas em diversos sítios podocitários: em moléculas envolvidas na fenda de filtração (slit diaphragm), por exemplo, nefrina, podocina e CD2AP; em moléculas do citoesqueleto podocitário, como a -actinina-4 e sinaptopodina; em moléculas marcadoras de diferenciação dos podócitos, como CD10 e WT-1; e ainda em marcadores de divisão celular como Ki-67 e PCNA. Os objetivos desse estudo foram: 1-) classificar as lesões morfológicas de GESF em biópsia renais nas 5 variantes da GESF propostas na Classificação de Columbia; e 2-) analisar a ocorrência de alterações moleculares podocitárias nestes casos. MÉTODOS: Foram selecionados 131 casos de biópsias renais com diagnóstico de GESF primária no período de 1996 a 2006. Os casos foram classificados de acordo com os critérios de Columbia e posteriormente submetidos a reações imuno-histoquímicas para os marcadores CD10, WT-1, vimentina, sinaptopodina, -actinina-4, GLEPP-1, citoqueratina 8/18, citoqueratina 19 e Ki-67. Os resultados foram submetidos à análise estatística através do teste qui-quadrado. RESULTADOS: A classificação das variantes da GESF se distribuiu da seguinte forma: 38,2% de variante NOS, 36,6% de variante COL, 14,5% de variante TIP, 6,9% de variante PHI e 3,8% de variante CEL. Os casos da variante COL se destacaram das demais variantes pela perda de expressão de marcadores de diferenciação celular, como o CD10 e o WT-1 (p<0,01), perda da molécula do citoesqueleto -actinina-4 (p<0,01) e neo-expressão de citoqueratinas 8-18 (p<0,05) e 19 (p<0,01). Adicionalmente, os casos das variantes COL e CEL se destacam das outras variantes pela expressão do marcador de divisão celular Ki-67 (p<0,05). CONCLUSÃO: a variante COL destacou-se das demais em relação às alterações moleculares observadas na análise imuno-histoquímica. O diagnóstico diferencial desta forma de GESF tem importância clínica por ela estar associada a pior evolução e prognóstico em relação às demais variantes. A integração destes marcadores na rotina diagnóstica pode auxiliar no diagnóstico diferencial da GESF COL / INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) is the most prevalent primary glomerulopathy in Brazil and its incidence is increasing worldwide. Primary FSGS is characterized clinically by affecting young people and causing severe proteinuria, often accompanied by nephrotic syndrome. The pathogenesis is related to podocyte injury, which may be due to several factors: viruses, drugs, immunological, etc. In 2004, the Columbia classification of FSGS identified five histological variants of the disease: collapsing (COL), usual (NOS), tip lesion (TIP), perihilar (PHI) and cellular variant (CEL). Several studies have demonstrated molecular changes in podocytes of FSGS patients, which were observed in molecules involved in the filtering function of these cells (nephrin, podocina and CD2AP), in podocyte cytoskeleton molecules (-actinin-4, and synaptopodin), as well as in molecular markers of podocyte differentiation (CD10 and WT-1) and of cell division (Ki-67 and PCNA). The aim of this study was to classify the FSGS biopsies according to the Columbia classification and to analyze the occurrence of molecular changes in the five morphological variants. METHODS: 131 cases of renal biopsies with a diagnosis of primary FSGS in the period 1996 to 2006 were classified according to the criteria of Columbia and then submitted to immunohistochemical reactions with the following antibodies: CD10, WT-1, Vimentin, Synaptopodin, -actinin-4, GLEPP-1, cytokeratin 8-18, cytokeratin 19, and Ki-67. RESULTS: FSGS cases were classified into five variants as follows: 38.2% of NOS variant, 36.6% COL, 14.5% TIP, 6.9% PHI and 3.8% CEL. The COL variant cases distinguished themselves among the other for having lost the expression of CD10 and WT-1 (p <0.01), and also of -actinin-4 (p <0, 01). Furthermore, they gained expression of the cytokeratin 8-18 (p <0.05) and 19 (p <0.01). The group of CEL and COL variants together differed from the other variants regarding the expression of cell division marker Ki-67 (p <0.05). CONCLUSION: COL variant of FSGS presents molecular changes that differs from others and can be demonstrated by immunohistochemistry. The differential diagnosis of this variant is important because of the worse clinical outcome and prognosis it presents in comparison with other variants. The identification of these markers by immunohistochemical on the routine practice may be useful in the diagnosis of COL FSGS

The International Accounting Standards Board (IASB) issued International Financial Reporting Standard No. 8 (IFRS 8) “Operating Segments” in November 2006 as a part of its convergence programme with the Financial Accounting Standards Board (FASB); the new standard became effective for periods beginning on or after 1/January/2009 (IASB, 2006a). IFRS 8 supersedes the previous international accounting standard (IAS): IAS 14 Revised (IAS 14R) “Segment Reporting” (IASC, 1997). IFRS 8 requires segments to be identified in accordance with the management approach. In particular, operating segments are to be identified on the basis of internal reports that are “regularly reviewed by the Chief Operating Decision Maker (CODM) to make decisions about resources to be allocated to the segment and assess its performance” (IASB, 2006a, para 5). There are two main objectives to this study: (i) to assess the impact of IFRS 8 on the segmental disclosures of Jordanian listed firms in their annual reports for 2009 when the standard became effective; and (ii) to explore the perceptions of external auditors, preparers and users (investors and analysts) of financial statements about this new segmental reporting standard. A decision usefulness theoretical framework underpins the research; the research was carried out by using a disclosure index analysis and semi-structured interviews. The two objectives of this thesis were investigated by employing these two methods; a disclosure index and semi-structured interviews. The research is located in Burrell and Morgan’s (1979) functionalist paradigm using a decision usefulness theory lens. The findings suggest that IFRS 8 has had a significant and sizeable impact on the segmental disclosure practices of Jordanian companies in 2009 compared to disclosure practices in annual reports for 2008 based on IAS 14R; a sample of reports for 109 first market Jordanian listed companies were investigated. The disclosure index findings indicate that the Jordanian listed companies provided more disaggregated segmental information, published data on additional segmental items and supplied new Entity-Wide Disclosures (EWDs) in accordance with IFRS 8’s management approach. For example, 10% of the sample companies provided segmental information for the first time in 2009. The Jordanian listed companies provided details about more disaggregated business segments (where the mean number of segments rose from 2.4 to 2.7) and geographic segments / EWDs (where xii the mean number of segments increased from 1.5 to 1.8). The average disclosure index score rose from 18.6% in 2008 to 30.6% in 2009. In addition, 27% of the sample companies went beyond the requirements of IFRS 8 by identifying the CODM in their annual reports for 2009. With regards to the semi-structured interviews, 31 participants agreed to provide their views on IFRS 8. The respondents indicated that the quantity and quality of segmental information provided under IFRS 8 in annual reports for 2009 was “better” than that disclosed in 2008; it was more understandable, relevant, reliable and comparable than the segmental information which had previously been reported. Their responses also indicated that the implementation of IFRS 8 did not appear to cause any difficulties for external auditors, preparers and users during 2009; most interviewees reported that IFRS 8 was not a problematic standard. They believed that the disclosure of segmental information increased, published segmental information became more organised and better explained and the segmental information disclosed was more transparent. The current study is the first of its kind in Jordan, and adds to the growing literature on financial disclosure; it therefore fills a gap about segmental disclosure in developing countries. It is also exploratory in nature, since very little is known about segmental reporting practices in Jordan. Thus, this study’s findings represent a significant contribution to knowledge.

The deployment of engineering models and design methods divorced from the effect that mechanised shield tunnelling with tunnel boring machines (TBMs) has on concrete segmental linings (CSLs) can lead to either material waste or structural damage within the tunnel design life. Most research to date on CSL behaviour during construction neglects the sequential ring loading and TBM-lining transverse interactions, which this thesis proved to be key in the short and long term behaviour of CSLs and whose study is essential if the design and maintenance of CSL structures is ever to be optimised. This thesis investigates the longitudinal and transverse behaviour of CSL structures simultaneously backfilled with bicomponent grouts (BGs) during tunnelling, and how this early response influences long term behaviour. The research work is drawn on three pillars that enable cross-validation of conclusions: analytical models, three-dimensional numerical simulations and the interpretation of the Crossrail's Thames tunnel (CTT) field data, which included distributed fibre optic strain (DFOS) data. A theoretical framework ranging from construction loading scenarios to the mechanisms underlying structural damage is described for the future development of limit state design methods. Analytical models of longitudinal behaviour are also proposed. The study of joint geometries, temporary spear bolts and DFOS sensing in CSL construction monitoring is included as ancillary research. The solution developed for a sequential elastic rod subjected to a trilinear temperature profile and in shear interaction with the elastic ground predicts accurately the early tunnel pre-stressing relaxation caused by grout hardening, e.g. ≈50% in the CTT. The proposed sequential elastic beam model, which incorporates the effects of stage-varying net TBM moments, transverse loads and lining pressure gradients within the tunnel unsupported length, estimates satisfactorily the history of tunnel beam response during construction for a realistic expression of the lining stiffness. A potential damage assessment method for the early detection of tunnel sections prone to ring joint damage was proposed. The TBM-lining transverse interaction determines the CSL ring behaviour at the early stages of tunnelling. The ring response resultant from this interaction is irrecoverable and contributes to the long term total deformations and internal forces; in tunnels excavated in grounds with Ko≈1, it becomes the major source of ring distortion. The main transverse actions are the sealing pressures, which are inversely related to the tail clearance, and the transverse load of oblique hydraulic jacks. When the non-bedded rings are eccentric with respect to the shield tail, the ring distortion increases the risk of cracking near the rear corners and spalling at the ram pad interspaces of constrained segments. The ring distortion is directly related to the pressure gradients, the unsupported length and the ring flexibility. When individual segments rotate outwards under the action of transverse ram loads, e.g. the outer springline segment during pronounced TBM steering around a horizontal curve, the localised action of the sealing pressures can result in longitudinal cracking at the intrados of the segment front. This study represents a qualitative leap towards the optimisation of CSL design, shifting the attention of researchers and designers to TBM-lining transverse interactions as the most determinant factor of structural response during construction in CSLs simultaneously backfilled with BGs.

Loss of the renal microvasculature is a common feature of almost all forms of chronic kidney disease (CKD). Here we explored the role of the angiogenic chemokine stromal cell-derived factor-1-alpha (SDF-1) and its cognate receptor CXCR4 in experimental and human CKD. CXCR4 was present on endothelial cells and podocytes, while SDF-1 was detectable on podocytes, arteriolar smooth muscle cells, interstitial fibroblasts and occasional endothelial cells. CXCR4 mRNA was elevated in the kidneys of rats with CKD and chronic antagonism of CXCR4 accelerated renal decline and capillary loss. Acute SDF-1 infusion activated glomerular endothelial nitric oxide synthase (eNOS) in vivo, while functional response to SDF-1 was impaired in glomerular endothelial cells derived from eNOS-/- mice. Finally, CXCR4 mRNA was also found to be increased in biopsies of patients with secondary focal segmental glomerulosclerosis. These observations indicate that local eNOS-dependent SDF-1/CXCR4 signaling exerts a compensatory reno-protective effect in the setting of CKD.

Loss of the renal microvasculature is a common feature of almost all forms of chronic kidney disease (CKD). Here we explored the role of the angiogenic chemokine stromal cell-derived factor-1-alpha (SDF-1) and its cognate receptor CXCR4 in experimental and human CKD. CXCR4 was present on endothelial cells and podocytes, while SDF-1 was detectable on podocytes, arteriolar smooth muscle cells, interstitial fibroblasts and occasional endothelial cells. CXCR4 mRNA was elevated in the kidneys of rats with CKD and chronic antagonism of CXCR4 accelerated renal decline and capillary loss. Acute SDF-1 infusion activated glomerular endothelial nitric oxide synthase (eNOS) in vivo, while functional response to SDF-1 was impaired in glomerular endothelial cells derived from eNOS-/- mice. Finally, CXCR4 mRNA was also found to be increased in biopsies of patients with secondary focal segmental glomerulosclerosis. These observations indicate that local eNOS-dependent SDF-1/CXCR4 signaling exerts a compensatory reno-protective effect in the setting of CKD.

The main objective of this thesis is to contribute to the prevention and control of the cardiovascular risk, hydration state and nutritional state in dialysis patients using non-invasive electrical impedance measurements. The thesis is structured in three parts with the following objectives: 1) to establish electrical impedance reference data for healthy Cuban population, 2)to improve the diagnostic based on impedance methods in Cuban hemodialysis (HD)patients and 3) to develop the impedance methods for continuous ambulatory peritoneal dialysis patients (CAPD).Healthy population: We analyzed the impedance vector distribution using the Bioimpedance Vector Analysis (BIVA) for the three more representative race-ethnicities in Cuba. We measured 1196 healthy adult (689 M, 507 W, 18-70 yr). The 95% confidence ellipses were drawn using specific BIVA software for mean vectors of different races. Due to the close distribution of mean vectors that we found for the three race-ethnicities, we concluded that only one set of sex-specific tolerance ellipses can be used for the Cuban population.HD patients: The BIVA method was used in a sample of 74 HD patients in stable (without edema) and critical (hyper-hydrated and malnutrition) states in order to establish the relation between hyper-hydration and mortality. Stable group include 48 patients (28 M and 18 W), and critical group include 28 critical patients (16 M and 12 W). Student's t test and Hotelling's T2 test were used to analyse the separation of groups obtained by means of clinical diagnosis and those obtained by BIVA. A statistically significant difference was obtained (P < 0.05) in R/H, Xc/H and phase angle, PA. Critical patients (hyper-hydrated and malnutrition) were located below the inferior pole of the 75% tolerance ellipse, with PA lower than 4º. In conclusion, the BIVA method could be used to detect hyper-hydration state before edema appears, and to predict survival through PA. Advantages of the method are its simplicity, objectivity and that it does not require the definition of a patient dry weight.CAPD patients: Segmental impedance measurements were obtained using 9 configurations (7 longitudinal and 2 transversal) in 25 CAPD male patients.In a first study we analyzed Z, Z/H and ZBMI indexes. 23 male patients were classified according to the hydration state as normo-hydrated, group 0 (10 M) or hyper-hydrated, group 1 (13 M). Wilcoxon test was used to analyze the change in impedance produced by a PD session. Mann-Whitney U test was used to analyse the separation between groups obtained by means of clinical diagnosis and those obtained by Z, Z/H or ZBMI. Spearman correlation was used to study the correlation between impedance vectors in each segment and clinical assessment. Statistical significance was set at P < 0.05. Results show that ZBMI gives information about the specific resistivity of tissues and not about fluid and fat mass changes. BIVA separate hyper-hydrated and normo-hydrated patients. Transversal measurements in the leg region and longitudinal in the thorax region are useful to corroborate the hydration and nutritional state in CAPD patients.In a second study a new classification was performed. Group 0 has normo-hydrated patients (10 M) and group 1 includes patients (15 M) with varying degrees of hypertension, overhydration and high score on cardiovascular risk factors. Mann-Whitney U-test was used to compare the differences in clinical measurements, laboratory test, and bioimpedance measurements between groups. The Mahalanobis Distance (dM2) was calculated using a bidimensional space, using the resistance measurement, right-side (RRS/H) or thorax segment (RTH/H) and the BPmean. Hotelling's T2 test was used to analyzed difference between groups through (RTH/H, BPmean) and (RRS/H, BPmean) vectors. A statistically significant difference was obtained (P < 0.05) in both vectors. Group 1 showed a small dM2 with respect to a reference patient (a critical patient with acute lung oedema) with high BPmean and low values of RTH/H and RRS/H. Moreover, Group 0 showed a larger dM2 with respect to the reference patient with lower BPmean and higher values of RTH/H and RRS/H. All patients classified as hyper-hydrated leading to hypertension by clinical assessment were correctly classified using dM2(RTH/H, BPmean). We conclude that segmental bioimpedance of the thoracic region could be a simple, objective, non-invasive method of support to facilitate the clinical assessment in CAPD.