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El proyecto de musealización del patrimonio del IES Isabel la Católica se remonta a 2006 cuando se empezó a recuperar el patrimonio del Instituto-Escuela, cuya Sección Retiro ocupó, entre 1928 y 1936, el edificio más antiguo de sus actuales instalaciones. Este ambicioso proyecto se inició con la ordenación y catalogación del archivo, la biblioteca y los laboratorios históricos de Biología y Geología del Instituto-Escuela, en los que se centralizó y se puso en valor el material conservado del experimento pedagógico que dicha institución llevó a cabo. Desde entonces, la biblioteca y los laboratorios históricos se convirtieron en espacios museísticos, donde se realizan actividades de difusión y uso didáctico del patrimonio del Instituto-Escuela. Después del paréntesis obligatorio de la pandemia, en 2021 continuó ese trabajo de recuperación, sumándole un nuevo proyecto: la catalogación y musealización del patrimonio del Instituto Isabel la Católica.

Yeng F Her,1 Eva Kubrova,2 Gabriel A Martinez Alvarez,2 Ryan S D’Souza1 1Department of Anesthesiology and Perioperative Medicine, Mayo Clinic Hospital, Rochester, MN, 55905, USA; 2Department of Physical Medicine and Rehabilitation, Mayo Clinic Hospital, Rochester, MN, 55905, USACorrespondence: Ryan S D’Souza, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA, Tel +507-284-9696, Email Dsouza.ryan@mayo.eduAbstract: Pain originating from the intervertebral disc (discogenic pain) is a prevalent manifestation of low back pain and is often challenging to treat. Of recent interest, regenerative medicine options with injectable biologics have been trialed in discogenic pain and a wide variety of other painful musculoskeletal conditions. In particular, the role of bone marrow aspirate concentrate (BMAC) and culture-expanded bone marrow derived mesenchymal stromal cells (BM-MSCs) in treating discogenic pain remains unclear. The primary objective of this systematic review was to appraise the evidence of intradiscal injection with BMAC and culture-expanded BM-MSCs in alleviating pain intensity from discogenic pain. Secondary outcomes included changes in physical function after intradiscal injection, correlation between stromal cell count and pain intensity, and anatomical changes of the disc assessed by radiographic imaging after intradiscal injection. Overall, 16 studies consisting of 607 participants were included in qualitative synthesis without pooling. Our synthesis revealed that generally intradiscal autologous or allogeneic BMAC and culture-expanded BM-MSCs improved discogenic pain compared to baseline. Intradiscal injection was also associated with improvements in physical functioning and positive anatomical changes on spine magnetic resonance imaging (improved disc height, disc water content, Pfirrmann grading) although anatomical findings were inconsistent across studies. However, the overall GRADEscore for this study was very low due to heterogeneity and poor generalizability. There were no serious adverse events reported post intradiscal injection except for a case of discitis.Keywords: BMAC, discogenic pain, bone marrow mesenchymal stromal cells

Microbial induced calcium carbonate precipitation (MICP) is widely investigated as a sustainable method of soil improvement. The pore-scale precipitation habit of calcium carbonate (CaCO3) and the grain-scale mechanical strength of the cementing bonds play a significant role in determining the mechanical response of MICP-treated soils. This study presents the pore-scale precipitation patterns in MICP-treated sands and the grain-scale cementation strength of two beads cemented by MICP. X-ray computed microtomography imaging of MICP-treated sands with different grain sizes reveal that the surface area, number of contacts, and flow-induced shear detachment as well as bacterial cell loci have a profound effect on the pore-scale precipitation. With different grain size, the precipitation can show either a contact-cementing pattern or a surface-coating habit. Particularly, evolution of the precipitation pattern is observed for large-sized grains from the surface-coating mode to the contact-cementing mode with an increase in CaCO3 content. The grain-scale mechanical strength tests on MICP-bonded bead pairs demonstrate that the failure with MICP bonding occurs in three modes: debonding, internal, and mixed failure modes. Amongst, the debonding failure mode has the greatest strength and the internal failure mode shows the lowest strength. The tensile strength is greater than the shear strength in all modes; particularly in debonding failure mode, the tensile strength of ~35 kPa and shear strength of ~13 kPa. The presented results advance our insight into pore-scale and grain-scale behavior of MICP-treated sands, which can be further extended to develop DEM models and transport models.

Recent studies focused on the shear behaviour of clay-structure interfaces have shown the importance of the shearing rate on the strength of these interfaces. In normally-consolidated clays, increasing the shearing rate results in a decrease in the interface strength, while the trend is opposite in heavily overconsolidated clays. While analytical and empirical interpretation methods indicate that the generation of shear-induced excess pore pressures are responsible for theaforementioned trends, experiments with pore water pressure measurements at the clay-structure interface are rare. In this paper, we first describe a modified interface shear box testing setup that is equipped with a pore water pressure sensor. For this equipment, the fully rough structural surface was manufactured with a port at the centre of the clay-surface interface to measure the pore water pressure. We present the results of undrained clay-structure interface tests on normally consolidated (NC) and overconsolidated (OC) specimens of kaolin clay. The results agree with the expectations, where the NC specimens generate excess pore pressures with greater magnitudes and heavily OC specimens generate negative excess pore pressures. Measurements of the pore water pressures allow calculating vertical effective stresses, which can be used to investigate the effective stress paths followed by the clay-structure interface during the tests. This paper also provides a comparison of the measured values of beta and adhesion factors with previously published results and relationships used for the design of deep foundations.

Well-graded soils can be found in nature and in engineered structures, such as dams and embankments. Prediction of their behavior is still an engineering challenge in part due to the lack of data in the literature, arguably due to difficulties associated in testing these soils in the laboratory and in situ. Particularly, there is still debate over the effect of the increased range of particle sizes (i.e., widening gradation) on the shear strength and dilatancy of coarse-grained soils. This paper presents the results of drained and undrained isotropically-consolidated triaxial compression tests on six soil mixes of varying gradation. These soils were sourced from a single natural deposit and selectively sieved and mixed to isolate the effects of gradation from those of particle shape and mineralogy. The results indicate that the critical state lines in void ratio – mean effective stress space move downward as the gradation becomes wider. For the same state parameter, the soils with a wider gradation exhibit greater dilatancy and generate negative excess pore pressures with greater magnitudes than the poorly-graded soils. In drained conditions, the greater dilatancy of the well-graded soils leads to greater peak friction angles, while in undrained conditions it leads to greater undrained shear strengths. The results show that these differences in behavior can only be captured when interpreting the results in terms of the state parameter and normalized state parameter, while comparing the results in terms of the void ratio or relative density obscures the effect of differences in gradation.

Spontaneous locking of the phase of a coherent phonon source to an external reference is demonstrated in a deeply sideband-unresolved optomechanical system. The high-amplitude mechanical oscillations are driven by the anharmonic modulation of the radiation pressure force that result from an absorption-mediated free-carrier/temperature limit cycle, i.e., self-pulsing. Synchronization is observed when the pump laser driving the mechanical oscillator to a self-sustained state is modulated by a radiofrequency tone. We employ a pump-probe phonon detection scheme based on an independent optical cavity to observe only the mechanical oscillator dynamics. The lock range of the oscillation frequency, i.e., the Arnold tongue, is experimentally determined over a range of external reference strengths, evidencing the possibility to tune the oscillator frequency for a range up to 350 kHz. The stability of the coherent phonon source is evaluated via its phase noise, with a maximum achieved suppression of 44 dBc/Hz at 1 kHz offset for a 100 MHz mechanical resonator. Introducing a weak modulation in the excitation laser reveals as a further knob to trigger, control and stabilize the dynamical solutions of self-pulsing based optomechanical oscillators, thus enhancing their potential as acoustic wave sources in a single-layer silicon platform.

Nanocrystalline materials exhibit properties that can differ substantially from those of their single crystal counterparts. As such, they provide ways to enhance and optimize their functionality for devices and applications. Here, we report on the optical, mechanical and thermal properties of nanocrystalline silicon probed by means of optomechanical nanobeams to extract information of the dynamics of optical absorption, mechanical losses, heat generation and dissipation. The optomechanical nanobeams are fabricated using nanocrystalline films prepared by annealing amorphous silicon layers at different temperatures. The resulting crystallite sizes and the stress in the films can be controlled by the annealing temperature and time and, consequently, the properties of the films can be tuned relatively freely, as demonstrated here by means of electron microscopy and Raman scattering. We show that the nanocrystallite size and the volume fraction of the grain boundaries play a key role in the dissipation rates through nonlinear optical and thermal processes. Promising optical (13,000) and mechanical (1700) quality factors were found in the optomechanical cavity realized in the nanocrystalline Si resulting from annealing at 950°C. The enhanced absorption and recombination rates via the intragap states and the reduced thermal conductivity boost the potential to exploit these nonlinear effects in applications including Nanoelectromechanical systems (NEMS), phonon lasing and chaos-based devices.

Cavity optomechanics has recently emerged as a new paradigm enabling the manipulation of mechanical motion via optical fields tightly confined in deformable cavities. When driving an optomechanical (OM) crystal cavity with a laser blue-detuned with respect to the optical resonance, the mechanical motion is amplified, ultimately resulting in phonon lasing at MHz and even GHz frequencies. In this work, we show that a silicon OM crystal cavity performs as an OM microwave oscillator when pumped above the threshold for self-sustained OM oscillations. To this end, we use an OM cavity designed to have a breathing-like mechanical mode at 3.897 GHz in a full phononic bandgap. Our measurements show that the first harmonic of the detected signal displays a phase noise of ≈−100 dBc/Hz at 100 kHz. Stronger blue-detuned driving leads eventually to the formation of an OM frequency comb, whose lines are spaced by the mechanical frequency. We also measure the phase noise for higher-order harmonics and show that, unlike in Brillouin oscillators, the noise is increased as corresponding to classical harmonic mixing. Finally, we present real-time measurements of the comb waveform and show that it can be fitted to a theoretical model recently presented. Our results suggest that silicon OM cavities could be relevant processing elements in microwave photonics and optical RF processing, in particular in disciplines requiring low weight, compactness and fiber interconnection.

Rolling bearings are an important part of rotary machines. They are used most widely in various mechanical sectors, which are among the most vulnerable components in machines. This paper uses CKF algorithm to compile a signal analysis system, analyses the vibration signal of the rolling bearing, extracts fault features, and realizes fault diagnosis. In order to improve the estimation accuracy of bearing fault diagnosis under nonlinear model, a nonlinear model of bearing fault diagnosis based on quaternion and low-accuracy high-noise sensors is established, and the attitude estimation has performed using the culture Kalman filter (CKF) algorithm. The sensor data comparison shows that the use of the volumetric Kalman filter algorithm can effectively improve the estimation accuracy of bearing fault diagnosis and stability. In this paper, the measured vibration signals of several groups of rolling bearings are analysed, and the signal characteristic frequency has extracted. The results show that using the analysis software designed in this paper, several typical faults of rolling bearings can be correctly identified.

Land use patterns of a river basin have a significant effect on the structure and function of river ecosystems. Changes in the composition of riparian plant communities modify the quantity, quality and seasonality of leaf–litter inputs, determining changes in macroinvertebrate colonization and activity. The main goal of this study was to test the effect of land–use modifications, and particularly the impact of eucalypt plantations, on the macroinvertebrate communities of sixteen headwater streams. Macroinvertebrates were counted and identified to family level. Land uses were classified in five categories using aerial photography: native forest, eucalypt plantations, agricultural land, shrubland, and urban areas. We found that macroinvertebrate diversity increased with basin size and with the proportion of basin covered by native forest. This variable correlated negatively with the land occupied by eucalypt plantations. Macroinvertebrate richness diminished with the increase of land surface covered by eucalypt plantations, and a similar tendency was observed with diversity. Furthermore, streams whose drainage basin was mainly covered by Eucalyptus were more likely to dry up in summer. This observation adds to evidence from previous studies that concluded that fast–growing tree plantations affect hydric resources, an important ecosystem service in the context of global warming. To minimize the impact of industrial sylviculture, we suggest that maintaining and/or restoring riparian forests could mitigate the effects of intensive eucalypt monocultures.

Introducción: Los factores psicosociales influyen en la calidad de vida de los profesionales de enfermería en el ámbito hospitalario asociados a variables sociodemográficas y laborales que repercuten en su calidad de vida.Objetivo: Analizar la calidad de vida laboral percibida por los profesionales de enfermería en un centro hospitalario, asociada a factores psicosociales y sociodemográficos.Metodología: Trabajo de campo descriptivo, observacional, cuantitativo, concurrente, transversal sobre calidad de vida. Muestra: profesionales de enfermería del ámbito hospitalario (N=240). El estudio realizado desde 2016 a 2018.Herramienta medición: cuestionario CVP-35, y datos sociodemográficos y laborales.Resultados: La satisfacción de los profesionales con la calidad de vida percibida (94%) es alta. Los porcentajes bajos se presentan en el apoyo directivo (48%). Existen asociaciones significativas (p

Energy piles and ground source heat pump systems have been shown to provide sustainable alternatives for temperature regulation in buildings and other applications such as road de-icing. However, their efficiency can be undermined in partially-saturated and dry sandy soils due to the relatively low thermal conductivity (kt) of these materials. Microbially-Induced Calcite Precipitation (MICP) has been demonstrated to be an environmentally-conscious ground improvement technology capable of modifying the engineering properties of sandy soils including increases in shear stiffness and strength and decreases in hydraulic conductivity. These improvements result from the precipitation of calcium carbonate crystals at inter-particle contacts and on particle surfaces. This paper presents results from a soil column study aimed at investigating changes in soil kt during MICP treatments and subsequent desaturation using a poorly- graded sand. The results indicate that while bio-cementation can increase soil kt, the level of enhancement depends on the degree of saturation. For instance, increases of up to 330% were measured under dry conditions while only modest increases of about 15% were measured under saturated conditions. MICP treatment may therefore be most effective at enhancing the kt of partially-saturated and dry sands. In addition, the similarity between the evolution of kt and shear wave velocity (Vs) during MICP treatment suggests that kt may provide a new method to assess cementation level and contact quality.

In this work we show that a silicon optomechanical crystal cavity can be used as an optomechanical oscillator when driven to the phonon lasing condition with a blue-detuned laser. The optomechanical cavity is designed to have a breathing like mode vibrating at Ωm/2π =3.897 GHz in a full phononic bandgap. Our measurements show that the first harmonic displays a phase noise of -100 dBc/Hz at 100 kHz. Stronger bluedetuned driving leads eventually to the formation of an optomechanical frequency comb, with lines spaced by the mechanical frequency. The measured phase noise grows up with the harmonic number, as in classical harmonic mixing. We present real-time measurements of the comb waveform and show that it can be adjusted to a theoretical model recently presented. Our results suggest that silicon optomechanical cavities can play a role in integrated microwave photonics.

Interfaces between geo-materials and soils play a critical role in a wide spectrum of geotechnical structures and soil/site characterization techniques in geotechnical engineering. Consequently, understanding the mechanics of interface shear behaviour at different scales can benefit both soil characterization and the design of geotechnical systems. This paper presents a series of numerical simulations that utilize the 3D discrete element modelling (DEM) technique and compares the results with those obtained from laboratory counterpart tests under axial and torsional axisymmetric interface shear. The difference observed in macro- and meso-scale responses under these loading conditions, such as shear strength, volumetric change, and shear zone characteristics are evaluated. In addition, responses at microscale including particle displacement trajectory, particles rotation, and local void ratio evolution are assessed allowing for links to the results obtained at larger spatial scales. These 3D numerical model studies expand the micromechanical processes under different shearing conditions previously presented by the authors from 2D to 3D space.

Typical soil-structure interfaces exhibit a response that is independent of loading direction due to the symmetry of the surfaces' profile. This study presents results from an experimental investigation on the response of sand specimens sheared against three types of surfaces bio-inspired from the skin along the underside of snakes. The results of shear box interface shear tests indicate that all three surfaces exhibit significant anisotropy in response in terms of mobilized shear resistances and corresponding volumetric changes. A discussion on the practical implications and potential benefits of implementation of the snake skin-inspired surfaces in engineering design is provided.

El concepto de deuda ecológica adquiere gran relevancia en el contexto del comercio internacional, donde no se cuantifica el deterioro ecológico, ni los daños ambientales asociados a la explotación de los recursos naturales y productos primarios exportados. Este debate es presentado en el presente artículo desde diferentes enfoques como es la deuda ecológica por emisiones de gases con efecto invernadero, los pasivos ambientales de las empresas, el comercio ecológicamente desigual, la exportación de residuos tóxicos desde el Norte, y la biopiratería, para hacer evidente la necesidad de llevar la economía mundial a un sendero más ecológico y más equitativo.

There are two principal ways of plot/exploitation management: Traditional or Conventional Managing (MC) and Precision viticulture (VP). Even though the technological requirements from these systems are different, in both cases, the Zoning or Variability Map for the Terroir (MVT) is required. MVT is a detailed mapping of the plot and enables to know the delineation and characterization of several sectors which make up its variability. The VP manages independently and optimized each of these sectors, allowing, among other things, optimizing the plantation's layout, rootstocks' selection, tillage, cover crop management, fertilization and maintenance programs, adjustment of water needs, diagnosis and pests and diseases management, monitoring of ripening, the harvest timing, etc. and all so in a localized manner according to the characteristics of each sector. Direct Method (MD) is the natural way to get the MVT. The map made from Direct Method defines and characterizes the different sectors indeed, and also provides some information about the terroir characteristics, which allow diagnosing the causes of heterogeneity and thus, handle them properly. Maps obtained by remote sensing from Spectral High Resolution Imaging (IEAR) provide relevant information, they are very affordable, and with an easy accuracy limits and they are obtained quicker than those made from MD. However, this kind of maps split the areas whose differentiation is due to the plant response in a specific situation that may be caused by a nearly endless options, and therefore, they vary with them. These maps are unable to discriminate sectors by the properties according to environmental factors (climate, lithology, geomorphology, soil) that affect the terroir variability, forbidding any direct action on them. Doing a MVT performed through a MD is expensive on large scales (very detailed studies) due to the gap about adequate perform delineations (net fixed error is related to sides length). However, IEAR technology provides a map which is obtained allowing to buffer this problem and also, reducing the costs. Both in maps obtained from MD or IEAR, the sampling quality is a key point. Both density of observations and the number of properties involved in the study determine its utility and the relative directives, when is possible under an international procedure (such as, OIV), must be a quality guarantee. In fact, both methodologies (MD and IEAR) are complementary for doing the MVT and, once the map (done through MD) is available, the right interpretations of the IEAR maps are possible, whether annual, seasonal, depending on the phenological status or any other circumstance that may affect the variability (pests, stress, ...). MVT obtained like that, allows to the viticulturist address the most ambitious goal: the product optimization and homogenization. Specifically, in a short or medium term and by the management carried out with the VP's performance on the terroir's properties in different sectors of the parcel/plot, resulting in the highest uniformity as possible, and also, in the product. In this work, we worked on terroir's variability and the vineyard management systems (MC and VP), highlighting the relevance of mapping, the need for MVT and its complementary performance related to the MD, and the use of remote sensing systems (IEAR) as another discriminative method.

Este artículo analiza la pobreza urbana desde la perspectiva de lavulnerabilidad social en cinco comunidades de la ciudad de Cali, pertenecientes a los estratos socioeconómicos 1, 2 y 3. El trabajo combinó la realización de encuestas con preguntas estructuradas y abiertas, y la recolección de relatos. La evidencia empírica muestra algunas situaciones de riesgo en estos hogares, en el contexto de la recesión económica experimentada en Colombia entre 1998 y 2004. Las estrategias identificadas, más frecuentes, fueron el endeudamiento, la reducción del gasto en alimentos y vestuario, y la incorporación laboral de otros miembros del hogar.

This article focuses on Rachel Seiffert’s The Dark Room (2001), which I place in the context of what Froma I. Zeitlin (2006) regards as an emerging trend in Holocaust literature: fictional stories that move away from the victims and focus instead on the victimisers, as well as on the impact and legacy of the Nazi period on average Germans. The Dark Room consists of three independent but related stories, entitled after each German protagonist, and taking place in Germany at different moments of the 20th century. It is my aim to analyse the themes that connect these three stories —loss, guilt, shame, secrets and deception, traumatic awakenings and the fall from innocence, the crisis of identity, etc.— and to relate them to the motif already suggested by the work’s title: photography. Pictures recur insistently throughout the book’s pages and, like the past, they constitute a spectral presence in Seiffert’s novella triptych, where photographs emerge as a vehicle for exploring the problems posed by photographic evidence. Thus, I argue, the thread that ultimately weaves the stories together has to do with each protagonist’s negative epiphany, that is to say, his/her painful discovery that, in spite of all that a picture can be said to capture or show, the truth turns out to be disturbingly absent, lying in an unreachable elsewhere, always beyond the frame.

Abstract Background Ovarian cancer is the most deadly gynecological cancer due to late diagnosis at advanced stage with major peritoneal involvement. To date most research has focused on primary tumor. However the prognosis is directly related to residual disease at the end of the treatment. Therefore it is mandatory to focus and study the biology of meatastatic disease that is most frequently localized to the peritoneal caivty in ovarian cancer. Methods We used high-density gene expression arrays to investigate gene expression changes between matched primary and metastatic (peritoneal) lesions. Results Here we show that gene expression profiles in peritoneal metastasis are significantly different than their matched primary tumor and these changes are affected by underlying copy number variation differences among other causes. We show that differentially expressed genes are enriched in specific pathways including JAK/STAT pathway, cytokine signaling and other immune related pathways. We show that underlying copy number variations significantly affect gene expression. Indeed patients with important differences in copy number variation displayed greater gene expression differences between their primary and matched metastatic lesions. Conclusions Our analysis shows a very specific targeting at both the genomic and transcriptomic level to upregulate certain pathways in the peritoneal metastasis of ovarian cancer. Moreover, while primary tumors use certain pathways we identify distinct differences with metastatic lesions. The variation between primary and metastatic lesions should be considered in personalized treatment of ovarian cancer.

Abstract The FAST project (Food Allergy Specific Immunotherapy) aims at the development of safe and effective treatment of food allergies, targeting prevalent, persistent and severe allergy to fish and peach. Classical allergen-specific immunotherapy (SIT), using subcutaneous injections with aqueous food extracts may be effective but has proven to be accompanied by too many anaphylactic side-effects. FAST aims to develop a safe alternative by replacing food extracts with hypoallergenic recombinant major allergens as the active ingredients of SIT. Both severe fish and peach allergy are caused by a single major allergen, parvalbumin (Cyp c 1) and lipid transfer protein (Pru p 3), respectively. Two approaches are being evaluated for achieving hypoallergenicity, i.e. site-directed mutagenesis and chemical modification. The most promising hypoallergens will be produced under GMP conditions. After pre-clinical testing (toxicology testing and efficacy in mouse models), SCIT with alum-absorbed hypoallergens will be evaluated in phase I/IIa and IIb randomized double-blind placebo-controlled (DBPC) clinical trials, with the DBPC food challenge as primary read-out. To understand the underlying immune mechanisms in depth serological and cellular immune analyses will be performed, allowing identification of novel biomarkers for monitoring treatment efficacy. FAST aims at improving the quality of life of food allergic patients by providing a safe and effective treatment that will significantly lower their threshold for fish or peach intake, thereby decreasing their anxiety and dependence on rescue medication.

Abstract Background A consistent line of investigation suggests that autonomic nervous system dysfunction may explain the multi-system features of fibromyalgia (FM); and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG) are key sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7) act as molecular gatekeepers for pain detection. Nav1.7 is encoded in gene SCN9A of chromosome 2q24.3 and is predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons. Several SCN9A sodium channelopathies have been recognized as the cause of rare painful dysautonomic syndromes such as paroxysmal extreme pain disorder and primary erythromelalgia. The aim of this study was to search for an association between fibromyalgia and several SCN9A sodium channels gene polymorphisms. Methods We studied 73 Mexican women suffering from FM and 48 age-matched women who considered themselves healthy. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Genomic DNA from whole blood containing EDTA was extracted by standard techniques. The following SCN9A single-nucleotide polymorphisms (SNP) were determined by 5' exonuclease TaqMan assays: rs4371369; rs4387806; rs4453709; rs4597545; rs6746030; rs6754031; rs7607967; rs12620053; rs12994338; and rs13017637. Results The frequency of the rs6754031 polymorphism was significantly different in both groups (P = 0.036) mostly due to an absence of the GG genotype in controls. Interestingly; patients with this rs6754031 GG genotype had higher FIQ scores (median = 80; percentile 25/75 = 69/88) than patients with the GT genotype (median = 63; percentile 25/75 = 58/73; P = 0.002) and the TT genotype (median = 71; percentile 25/75 = 64/77; P = 0.001). Conclusion In this ethnic group; a disabling form of FM is associated to a particular SCN9A sodium channel gene variant. These preliminary results raise the possibility that some patients with severe FM may have a dorsal root ganglia sodium channelopathy.

Abstract Background Globalisation has prompted countries to evaluate their position on trade in health services. However, this is often done from a multi-lateral, rather than a regional or bi-lateral perspective. In a previous review, we concluded that most of the issues raised could be better addressed from a bi-lateral relationship. We report here the results of a qualitative exercise to assess stakeholders' perceptions on the prospects for such a bi-lateral system, and its ability to address concerns associated with medical tourism. Methods 30 semi-structured interviews were carried out with stakeholders, 20 in India and 10 in the UK, to assess their views on the potential offered by a bi-lateral relationship on medical tourism between both countries. Issues discussed include data availability, origin of medical tourists, quality and continuity of care, regulation and litigation, barriers to medical tourism, policy changes needed, and prospects for such a bi-lateral relationship. Results The majority of stakeholders were concerned about the quality of health services patients would receive abroad, regulation and litigation procedures, lack of continuity of care, and the effect of such trade on the healthcare available to the local population in India. However, when considering trade from a bi-lateral point of view, there was disagreement on how these issues would apply. There was further disagreement on the importance of the Diaspora and the validity of the UK's 'rule' that patients should not fly more than three hours to obtain care. Although the opinion on the prospects for an India-UK bi-lateral relationship was varied, there was no consensus on what policy changes would be needed for such a relationship to take place. Conclusions Whilst the literature review previously carried out suggested that a bi-lateral relationship would be best-placed to address the concerns regarding medical tourism, there was scepticism from the analysis provided in this paper based on the over-riding feeling that the political 'cost' involved was likely to be the major impediment. This makes the need for better evidence even more acute, as much of the current policy process could well be based on entrenched ideological positions, rather than secure evidence of impact.

Abstract Background Improvements in communication and information technologies have allowed for the globalisation of health services, especially the provision of health services from other countries, such as the use of telemedicine. This has led countries to evaluate their position on whether and to what extent they should open their health systems to trade. This often takes place from the context of multi-lateral trade agreements (under the auspices of the World Trade Organisation), which is misplaced as a significant amount of trade takes place regionally or bi-laterally. We report here the results of a qualitative study assessing stakeholders' views on the potential for a bi-lateral trade relationship between India and the UK, where India acts as an exporter and the UK as an importer of telemedicine services. Methods 19 semi-structured interviews were carried out with stakeholders from India and the UK. The themes discussed include prospects on the viability of a bi-lateral relationship between the UK and India on telemedicine, current activities and operations, barriers, benefits and risks. Results The participants in general believed there were good prospects for telemedicine trade, and that this could bring benefits to "importing" countries in terms of cost-savings and faster delivery of care and to "exporting" countries in the form of foreign exchange and quality improvement. However, there were some concerns regarding quality of care, regulation, accreditation and data security. Conclusions There is potential for trade in this type of health services to succeed and bring about important benefits to the countries involved. However, issues around data security and accreditation need to be taken into consideration. Countries may wish to consider entering bi-lateral agreements, as they provide more potential to address the concerns and capitalise on the benefits. Finally, this paper concludes that more data should be collected, both on the volume of telemedicine trade and on the impact it is having on health systems, as currently there is very limited data on this.

Abstract Background The Mycobacterium leprae genome has less than 50% coding capacity and 1,133 pseudogenes. Preliminary evidence suggests that some pseudogenes are expressed. Therefore, defining pseudogene transcriptional and translational potentials of this genome should increase our understanding of their impact on M. leprae physiology. Results Gene expression analysis identified transcripts from 49% of all M. leprae genes including 57% of all ORFs and 43% of all pseudogenes in the genome. Transcribed pseudogenes were randomly distributed throughout the chromosome. Factors resulting in pseudogene transcription included: 1) co-orientation of transcribed pseudogenes with transcribed ORFs within or exclusive of operon-like structures; 2) the paucity of intrinsic stem-loop transcriptional terminators between transcribed ORFs and downstream pseudogenes; and 3) predicted pseudogene promoters. Mechanisms for translational "silencing" of pseudogene transcripts included the lack of both translational start codons and strong Shine-Dalgarno (SD) sequences. Transcribed pseudogenes also contained multiple "in-frame" stop codons and high Ka/Ks ratios, compared to that of homologs in M. tuberculosis and ORFs in M. leprae. A pseudogene transcript containing an active promoter, strong SD site, a start codon, but containing two in frame stop codons yielded a protein product when expressed in E. coli. Conclusion Approximately half of M. leprae's transcriptome consists of inactive gene products consuming energy and resources without potential benefit to M. leprae. Presently it is unclear what additional detrimental affect(s) this large number of inactive mRNAs has on the functional capability of this organism. Translation of these pseudogenes may play an important role in overall energy consumption and resultant pathophysiological characteristics of M. leprae. However, this study also demonstrated that multiple translational "silencing" mechanisms are present, reducing additional energy and resource expenditure required for protein production from the vast majority of these transcripts.

Abstract Backgroung Biodegradable plastics can be made from polylactate, which is a polymer made from lactic acid. This compound can be produced from renewable resources as substrates using microorganisms. Bacillus subtilis is a Gram-positive bacterium recognized as a GRAS microorganism (generally regarded as safe) by the FDA. B. subtilis produces and secretes different kind of enzymes, such as proteases, cellulases, xylanases and amylases to utilize carbon sources more complex than the monosaccharides present in the environment. Thus, B. subtilis could be potentially used to hydrolyze carbohydrate polymers contained in lignocellulosic biomass to produce chemical commodities. Enzymatic hydrolysis of the cellulosic fraction of agroindustrial wastes produces cellobiose and a lower amount of glucose. Under aerobic conditions, B. subtilis grows using cellobiose as substrate. Results In this study, we proved that under non-aerated conditions, B. subtilis ferments cellobiose to produce L-lactate with 82% of the theoretical yield, and with a specific rate of L-lactate production similar to that one obtained fermenting glucose. Under fermentative conditions in a complex media supplemented with glucose, B. subtilis produces L-lactate and a low amount of 2,3-butanediol. To increase the L-lactate production of this organism, we generated the B subtilis CH1 alsS- strain that lacks the ability to synthesize 2,3-butanediol. Inactivation of this pathway, that competed for pyruvate availability, let a 15% increase in L-lactate yield from glucose compared with the parental strain. CH1 alsS- fermented 5 and 10% of glucose to completion in mineral medium supplemented with yeast extract in four and nine days, respectively. CH1 alsS- produced 105 g/L of L-lactate in this last medium supplemented with 10% of glucose. The L-lactate yield was up to 95% using mineral media, and the optical purity of L-lactate was of 99.5% since B. subtilis has only one gene (lctE) that exclusively encodes a L-lactate deshydrogenase. Conclusion This study shows that by taking advantage of the cellobiose utilization capability and osmotic stress high resistance of B. subtilis, a robust process for L-lactate production can be developed.

Abstract Background Anthranilate is an aromatic amine used industrially as an intermediate for the synthesis of dyes, perfumes, pharmaceuticals and other classes of products. Chemical synthesis of anthranilate is an unsustainable process since it implies the use of nonrenewable benzene and the generation of toxic by-products. In Escherichia coli anthranilate is synthesized from chorismate by anthranilate synthase (TrpED) and then converted to phosphoribosyl anthranilate by anthranilate phosphoribosyl transferase to continue the tryptophan biosynthetic pathway. With the purpose of generating a microbial strain for anthranilate production from glucose, E. coli W3110 trpD9923, a mutant in the trpD gene that displays low anthranilate producing capacity, was characterized and modified using metabolic engineering strategies. Results Sequencing of the trpED genes from E. coli W3110 trpD9923 revealed a nonsense mutation in the trpD gene, causing the loss of anthranilate phosphoribosyl transferase activity, but maintaining anthranilate synthase activity, thus causing anthranilate accumulation. The effects of expressing genes encoding a feedback inhibition resistant version of the enzyme 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (aroGfbr), transketolase (tktA), glucokinase (glk) and galactose permease (galP), as well as phosphoenolpyruvate:sugar phosphotransferase system (PTS) inactivation on anthranilate production capacity, were evaluated. In shake flask experiments with minimal medium, strains W3110 trpD9923 PTS- and W3110 trpD9923/pJLBaroGfbrtktA displayed the best production parameters, accumulating 0.70–0.75 g/L of anthranilate, with glucose-yields corresponding to 28–46% of the theoretical maximum. To study the effects of extending the growth phase on anthranilate production a fed-batch fermentation process was developed using complex medium, where strain W3110 trpD9923/pJLBaroGfbrtktA produced 14 g/L of anthranilate in 34 hours. Conclusion This work constitutes the first example of a microbial system for the environmentally-compatible synthesis of anthranilate generated by metabolic engineering. The results presented here, including the characterization of mutation in the trpD gene from strain W3110 trpD9923 and the development of a fermentation strategy, establish a step forward towards the future improvement of a sustainable process for anthranilate production. In addition, the present work provides very useful data regarding the positive and negative consequences of the evaluated metabolic engineering strategies.

Abstract Background Selenoprotein S (SelS) protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component. Results Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171) were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study. Conclusion Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.

Abstract Background Microarray-based tumor classification is characterized by a very large number of features (genes) and small number of samples. In such cases, statistical techniques cannot determine which genes are correlated to each tumor type. A popular solution is the use of a subset of pre-specified genes. However, molecular variations are generally correlated to a large number of genes. A gene that is not correlated to some disease may, by combination with other genes, express itself. Results In this paper, we propose a new classiification strategy that can reduce the effect of over-fitting without the need to pre-select a small subset of genes. Our solution works by taking advantage of the information embedded in the testing samples. We note that a well-defined classification algorithm works best when the data is properly labeled. Hence, our classification algorithm will discriminate all samples best when the testing sample is assumed to belong to the correct class. We compare our solution with several well-known alternatives for tumor classification on a variety of publicly available data-sets. Our approach consistently leads to better classification results. Conclusion Studies indicate that thousands of samples may be required to extract useful statistical information from microarray data. Herein, it is shown that this problem can be circumvented by using the information embedded in the testing samples.

Abstract Background A metabolic regulation study was performed, based upon measurements of enzymatic activities, fermentation performance, and RT-PCR analysis of pathways related to central carbon metabolism, in an ethanologenic Escherichia coli strain (CCE14) derived from lineage C. In comparison with previous engineered strains, this E coli derivative has a higher ethanol production rate in mineral medium, as a result of the elevated heterologous expression of the chromosomally integrated genes encoding PDCZm and ADHZm (pyruvate decarboxylase and alcohol dehydrogenase from Zymomonas mobilis). It is suggested that this behavior might be due to lineage differences between E. coli W and C. Results This study demonstrated that the glycolytic flux is controlled, in this case, by reactions outside glycolysis, i.e., the fermentative pathways. Changes in ethanol production rate in this ethanologenic strain result in low organic acid production rates, and high glycolytic and ethanologenic fluxes, that correlate with enhanced transcription and enzymatic activity levels of PDCZm and ADHZm. Furthermore, a higher ethanol yield (90% of the theoretical) in glucose-mineral media was obtained with CCE14 in comparison with previous engineered E. coli strains, such as KO11, that produces a 70% yield under the same conditions. Conclusion Results suggest that a higher ethanol formation rate, caused by ahigher PDCZm and ADHZm activities induces a metabolic state that cells compensate through enhanced glucose transport, ATP synthesis, and NAD-NADH+H turnover rates. These results show that glycolytic enzymatic activities, present in E. coli W and C under fermentative conditions, are sufficient to contend with increases in glucose consumption and product formation rates.

Abstract Background The etiology of Ulcerative Colitis (UC) and Crohn's Disease (CD), considered together as Inflammatory Bowel Diseases (IBD), involves environmental and genetic factors. Although some genes are already known, the genetics underlying these diseases is complex and new candidates are continuously emerging. The CD209 gene is located in a region linked previously to IBD and a CD209 functional polymorphism (rs4804803) has been associated to other inflammatory conditions. Our aim was to study the potential involvement of this CD209 variant in IBD susceptibility. Methods We performed a case-control study with 515 CD patients, 497 UC patients and 731 healthy controls, all of them white Spaniards. Samples were typed for the CD209 single nucleotide polymorphism (SNP) rs4804803 by TaqMan technology. Frequency comparisons were performed using χ2 tests. Results No association between CD209 and UC or CD was observed initially. However, stratification of UC patients by HLA-DR3 status, a strong protective allele, showed that carriage of the CD209_G allele could increase susceptibility in the subgroup of HLA-DR3-positive individuals (p = 0.03 OR = 1.77 95% CI 1.04–3.02, vs. controls). Conclusion A functional variant in the CD209 gene, rs4804803, does not seem to be influencing Crohn's disease susceptibility. However, it could be involved in the etiology or pathology of Ulcerative Colitis in HLA-DR3-positive individuals but further studies are necessary.

Abstract Background The protein tyrosine phosphatase N22 gene (PTPN22) encodes a lymphoid-specific phosphatase (LYP) which is an important downregulator of T cell activation. A PTPN22 polymorphism, C1858T, was found associated with type 1 diabetes (T1D) in different Caucasian populations. In this study, we aimed at confirming the role of this variant in T1D predisposition in the Spanish population. Methods A case-control was performed with 316 Spanish white T1D patients consecutively recruited and 554 healthy controls, all of them from the Madrid area. The PTPN22 C1858T SNP was genotyped in both patients and controls using a TaqMan Assay in a 7900 HT Fast Real-Time PCR System. Results We replicated for the first time in a Spanish population the association of the 1858T allele with an increased risk for developing T1D [carriers of allele T vs. CC: OR (95%) = 1.73 (1.17–2.54); p = 0.004]. Furthermore, this allele showed a significant association in female patients with diabetes onset before age 16 years [carriers of allele T vs. CC: OR (95%) = 2.95 (1.45–6.01), female patients vs female controls p = 0.0009]. No other association in specific subgroups stratified for gender, HLA susceptibility or age at onset were observed. Conclusion Our results provide evidence that the PTPN22 1858T allele is a T1D susceptibility factor also in the Spanish population and it might play a different role in susceptibility to T1D according to gender in early-onset T1D patients.

Abstract Background To correlate the metabolic changes with size changes for tumor response by concomitant PET-CT evaluation of lung cancers after radiotherapy. Methods 36 patients were studied pre- and post-radiotherapy with18FDG PET-CT scans at a median interval of 71 days. All of the patients were followed clinically and radiographically after a mean period of 342 days for assessment of local control or failure rates. Change in size (sum of maximum orthogonal diameters) was correlated with that of maximum standard uptake value (SUV) of the primary lung cancer before and after conventional radiotherapy. Results There was a significant reduction in both SUV and size of the primary cancer after radiotherapy (p < 0.00005). Among the 20 surviving patients, the sensitivity, specificity, and accuracy using PET (SUV) were 94%, 50%, 90% respectively and the corresponding values using and CT (size criteria) were 67%, 50%, and 65% respectively. The metabolic change (SUV) was highly correlated with the change in size by a quadratic function. In addition, the mean percentage metabolic change was significantly larger than that of size change (62.3 ± 32.7% vs 47.1 ± 26.1% respectively, p = 0.03) Conclusion Correlating and incorporating metabolic change by PET into size change by concomitant CT is more sensitive in assessing therapeutic response than CT alone.

Abstract Background Type 1 diabetes (T1D) is a chronic, autoimmune and multifactorial disease characterized by abnormal metabolism of carbohydrate and fat. Diminished carnitine plasma levels have been previously reported in T1D patients and carnitine increases the sensitivity of the cells to insulin. Polymorphisms in the carnitine transporters, encoded by the SLC22A4 and SLC22A5 genes, have been involved in susceptibility to two other autoimmune diseases, rheumatoid arthritis and Crohn's disease. For these reasons, we investigated for the first time the association with T1D of six single nucleotide polymorphisms (SNPs) mapping to these candidate genes: slc2F2, slc2F11, T306I, L503F, OCTN2-promoter and OCTN2-intron. Methods A case-control study was performed in the Spanish population with 295 T1D patients and 508 healthy control subjects. Maximum-likelihood haplotype frequencies were estimated by applying the Expectation-Maximization (EM) algorithm implemented by the Arlequin software. Results When independently analyzed, one of the tested polymorphisms in the SLC22A4 gene at 1672 showed significant association with T1D in our Spanish cohort. The overall comparison of the inferred haplotypes was significantly different between patients and controls (χ2 = 10.43; p = 0.034) with one of the haplotypes showing a protective effect for T1D (rs3792876/rs1050152/rs2631367/rs274559, CCGA: OR = 0.62 (0.41–0.93); p = 0.02). Conclusion The haplotype distribution in the carnitine transporter locus seems to be significantly different between T1D patients and controls; however, additional studies in independent populations would allow to confirm the role of these genes in T1D risk.

Abstract Background IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. Genetic and environmental factors are suspected to be involved in the development of the disease. Interleukin-10 (IL-10) is a cytokine with stimulatory activity on immunoglobulin production and it may be an important regulator in IgAD pathogenesis. The IL-10 gene contains several single nucleotide polymorphisms (SNPs) and two polymorphic microsatellites located in the 5'-flanking region. Our aim was to ascertain if any of these polymorphic markers are associated or linked to IgAD in Spanish patients. Methods We genotyped 278 patients with IgAD and 573 ethnically matched controls for the microsatellites IL-10R and IL-10G and for three single nucleotide polymorphisms at positions -1082, -819 and -592 in the proximal promoter of the gene. We also included in this study the parents of 194 patients in order to study the IL-10 haplotypes transmitted and not transmitted to the affected offspring. Results The only allele where a significant difference was observed in the comparison between IgA deficiency patients and controls was the IL-10G12 allele (OR = 1.58 and p = 0.021). However, this p value could not withstand a Bonferroni correction. None of the IL-10R or promoter SNP alleles was found at a different frequency when patients were compared with controls. Conclusion Our data do not show any significant difference in IL-10 polymorphism frequencies between control and IgAD patient samples. Their haplotype distribution among patients and controls was also equivalent and therefore these microsatellites and SNPs do not seem to influence IgAD susceptibility.

Abstract Background The 1858C/T SNP of the PTPN22 gene has been associated with many autoimmune diseases, suggesting the existence of an inflammatory process common to all of them. We studied the association of that polymorphism with immunoglobulin A deficiency (IgAD) following a double approach: a case-control and a TDT study. Methods A total of 259 IgAD patients and 455 unrelated matched controls, and 128 families were used for each approach. Comparisons were performed using Chi-Square tests or Fisher's exact test when necessary. Results No association between the PTPN22 1858C/T SNP and IgA deficiency was found in any case (allelic frequencies 8% vs. 6% in patients and controls, respectively, OR= 1.14 (0.72–1.79), p= 0.56; TDT p = 0.08). Conclusion The result obtained seems to reinforce the consideration of IgA deficiency as a primary immunodeficiency rather than an autoimmune disease.

Abstract Background Celiac disease (CD) is a chronic disorder characterized by a pathological inflammatory response after exposure to gluten in genetically susceptible individuals. The HLA complex accounts for less than half of the genetic component of the disease, and additional genes must be implicated. Interleukin-10 (IL-10) is an important regulator of mucosal immunity, and several reports have described alterations of IL-10 levels in celiac patients. The IL-10 gene is located on chromosome 1, and its promoter carries several single nucleotide polymorphisms (SNPs) and microsatellites which have been associated to production levels. Our aim was to study the role of those polymorphisms in susceptibility to CD in our population. Methods A case-control and a familial study were performed. Positions -1082, -819 and -592 of the IL-10 promoter were typed by TaqMan and allele specific PCR. IL10R and IL10G microsatellites were amplified with labelled primers, and they were subsequently run on an automatic sequencer. In this study 446 patients and 573 controls were included, all of them white Spaniards. Extended haplotypes encompassing microsatellites and SNPs were obtained in families and estimated in controls by the Expectation-Maximization algorithm. Results No significant associations after Bonferroni correction were observed in the SNPs or any of the microsatellites. Stratification by HLA-DQ2 (DQA1*0501-DQB1*02) status did not alter the results. When extended haplotypes were analyzed, no differences were apparent either. Conclusion The IL-10 polymorphisms studied are not associated with celiac disease. Our data suggest that the IL-10 alteration seen in patients may be more consequence than cause of the disease.

Abstract Background The etiology of multiple sclerosis (MS) is at present not fully elucidated, although it is considered to result from the interaction of environmental and genetic susceptibility factors. In this work we aimed at testing the Early B-cell Factor (EBF1) gene as a functional and positional candidate risk factor for this neurological disease. Axonal damage is a hallmark for multiple sclerosis clinical disability and EBF plays an evolutionarily conserved role in the expression of proteins essential for axonal pathfinding. Failure of B-cell differentiation was found in EBF-deficient mice and involvement of B-lymphocytes in MS has been suggested from their presence in cerebrospinal fluid and lesions of patients. Methods The role of the EBF1 gene in multiple sclerosis susceptibility was analyzed by performing a case-control study with 356 multiple sclerosis patients and 540 ethnically matched controls comparing the EBF1 polymorphism rs1368297 and the microsatellite D5S2038. Results Significant association of an EBF1-intronic polymorphism (rs1368297, A vs. T: p = 0.02; OR = 1.26 and AA vs. [TA+TT]: p = 0.02; OR = 1.39) was discovered. This association was even stronger after stratification for the well-established risk factor of multiple sclerosis in the Major Histocompatibility Complex, DRB1*1501 (AA vs. [TA+TT]: p = 0.005; OR = 1.78). A trend for association in the case-control study of another EBF1 marker, the allele 5 of the very informative microsatellite D5S2038, was corroborated by Transmission Disequilibrium Test of 53 trios (p = 0.03). Conclusion Our data support EBF1 gene association with MS pathogenesis in the Spanish white population. Two genetic markers within the EBF1 gene have been found associated with this neurological disease, indicative either of their causative role or that of some other polymorphism in linkage disequilibrium with them.

Abstract Background The Major Histocompatibility Complex is the main genetic contributor to susceptibility to type 1 diabetes (T1D); genome-wide scans have consistently mapped increased predisposition to this region. The highest disease risk has been associated with HLA-DR3 and HLA-DR4. In particular, the DR3-positive ancestral haplotype 18.2 was reported as highly diabetogenic. We aimed to corroborate whether this haplotype increases the susceptibility conferred by the DQ2-DR3 alleles in a Mediterranean population. We also searched for additional susceptibility factors to the classic DQ2-DR3 and DQ8-DR4. Results Genetic MHC markers were analysed in a case-control study with 302 T1D patients and 529 ethnically matched controls. DR3-TNFa1b5 carrier rate was significantly higher in DR3-positive heterozygous T1D patients than in DR3-positive heterozygous controls (p = 0.0019; odds ratio OR [95% confidence interval CI] = 2.26 [1.3–3.93]). This data was confirmed analysing the allelic frequency, which includes the information corresponding to the DR3-homozygous individuals (p = 0.001; OR = 2.09) and by using the Arlequin software to check the DR3-positive haplotypes (p = 0.004;OR = 1.93). The present results provide strong evidence of a second susceptibility region in the ancestral haplotype 18.2 in the Spanish population. Moreover, we searched for T1D susceptibility factors in addition to the MHC classical ones, within the DR2-DQ6/DR3-DQ2/DR4-DQ8 negative population. Several genetic markers in both MHC class II (DQA1*0101-DQB1*0501 [p = 0.007;OR = 2.81], DQA1*0201-DQB1*0202 [p = 0.03; OR = 2.35]) and III (TNFa2b1 [p = 0.01 OR = 2.74], BAT-2*2 [p = 0.004; OR = 3.19]) were found. These different alleles associated with T1D were not independent and we observed linkage disequilibrium among them leading us to describe two new risk haplotypes (DQA1*0101-DQB1*0501-TNFa2b1 and DQA1*0201-DQB1*0202- BAT-2*2). Finally, we studied a T1D susceptibility/protection marker located in extended class I, D6S2223; however, no association was observed in our population. Conclusion Our results suggest that other associated MHC haplotypes might present susceptibility factors in loci different from HLA-class II and that the class II molecules are not necessarily the universal etiologic factor in every MHC haplotype.

This article proposes an analysis of Peter Ackroyd's The House of Doctor Dee (1993) in the light of two different dichotomies: Brian McHale's epistemological (cognitive) / ontological (postcognitive) dominant and John Vernon's garden / map dynamics. The House of Doctor Dee is constructed around a series of strategies closely related to the postcognitive worldview, strategies which have come to be associated with postmodernist aesthetics and which can as well be regarded as confirming and developing ideas and devices already present in previous works by the same author. Significantly, the techniques in what McHale calls the postmodernist repertoire can be said to be based on the same integrative principle that rules Vernon's garden, the latter being an image of wholeness which stands in direct opposition to the splitting rationale of the map. Vernon's dynamics of integration, together with McHale's ontological structures, become in my analysis the key to understanding Ackroyd's novel, while simultaneously suggesting an interesting perspective from which to approach postmodernist literature as a whole.