Evolutionary analysis of genetic variants involved in rare diseases

Next-generation sequencing techniques such as exome sequencing can successfully detect all genetic variants in a human exome and it has been useful together with the implementation of variant filters to identify causing-disease mutations. Two filters aremainly used for the mutations identification: low allele frequency and the computational annotation of the genetic variant. Bioinformatic tools to predict the effect of a givenvariant may have errors due to the existing bias in databases and sometimes show a limited coincidence among them. Advances in functional and comparative genomics are needed in order to properly annotate these variants.The goal of this study is to: first, functionally annotate Common Variable Immunodeficiency disease (CVID) variants with the available bioinformatic methods in order to assess the reliability of these strategies. Sencondly, as the development of new methods to reduce the number of candidate genetic variants is an active and necessary field of research, we are exploring the utility of gene function information at organism level as a filter for rare disease genes identification. Recently, it has been proposed that only 10-15% of human genes are essential and therefore we would expect that severe rare diseases are mostly caused by mutations on them. Our goal is to determine whether or not these rare and severe diseases are caused by deleterious mutations in these essential genes. If this hypothesis were true, taking into account essential genes as a filter would be an interesting parameter to identify causingdisease mutations.

Buccodental health and oral mucositis. Clinical study in patients with hematological diseases

Objectives: The objective of the present study is to assess whether a good buccodental status (evaluated by means of dentogingival indices), is associated with a lower incidence and severity of oral mucositis in patients with hematological diseases who receive treatment with chemotherapy or bone marrow transplant. Study design: The study was carried out on 97 patients admitted to the Hematology Service of the Hospital Duran y Reynals in Barcelona during 2002-2003. These patients received treatment with chemotherapy or conditioning prior to bone marrow transplant. A descriptive study was made, analyzing oral hygiene, one dental index, and two gingivales indices, and evaluating their relationship with the appearance of mucositis. Results: The patients with high plaque (PI) and gingival (GI) indices during chemotherapy presented a higher percentage of mucositis (77.4% and 65.7% respectively) against those who had little or no visible plaque. In the case of the PI, the differences were statistically significant (p=0.015). Likewise, patients who brushed their teeth 3 times/day presented mucositis in only 26.7% of cases, against those who did not brush, or brushed only once a day (65.9% and 68.4%), these differences also being statistically significant (p=0.013). The CAO showed similar results in patients with or without mucositis (7.59 and 7.03 respectively). Conclusions: In our study, a good gingival status as well as good oral hygiene during chemoradiotherapy is associated with a lower incidence and severity of mucositis.

The origins and impact of primate segmental duplications

Duplicated sequences are substrates for the emergence of new genes and are an important source of genetic instability associated with rare and common diseases. Analyses of primate genomes have shown an increase in the proportion of interspersed segmental duplications (SDs) within the genomes of humans and great apes. This contrasts with other mammalian genomes that seem to have their recently duplicated sequences organized in a tandem configuration. In this review, we focus on the mechanistic origin and impact of this difference with respect to evolution, genetic diversity and primate phenotype. Although many genomes will be sequenced in the future, resolution of this aspect of genomic architecture still requires high quality sequences and detailed analyses.

Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.568.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 24 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 1230months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.57,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

BAPNE method and N eurorehabilitation in patients with severe acquired brain injury

The use of body percussion through BAPNE method in neurorehabilitation offers the possibility of studying the development of motor skills, attention, coordination, memory and social interaction of patients with neurological diseases. The experimental protocol was carried out on 52 patients with severe acquired brain injury. Patients were selected for the cut - off scores in the standard neuropsychologic al tests of sustained attention , divided and alert ; at least one emisoma intact, cut -off scores in the standard for procedural and semantic memory ; eye sight , hearing and speech intact. The first group of patients has supported the protocol BAPNE tougher with the traditional rehabilitation activities . The control group continued to perform exclusively the cognitive and neuromotor rehabilitation according to traditional protocols. At 6 months after administration of the protocol is expected to re-test to assess if present , the maintenance of the effects of rehabilitation obtained. Experimentation is carried out for 10 weeks following the protocol of BAPNE method in the Roboris Foundation of Rome.

Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.5-7,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

Further insights in trichothiodistrophy: a clinical, microscopic, and ultrastructural study of 20 cases and literature review

Background: Trichothiodistrophy (TTD) is a rare autosomal recessive condition that is characterized by a specific congenital hair shaft dysplasia caused by deficiency of sulfur associated with a wide spectrum of multisystem abnormalities. In this article, we study clinical, microscopic, and ultrastructural findings of 20 patients with TTD with the aim to add further insights regarding to this rare condition. Additionally, analyses of our results are compared with those extracted from the literature in order to enhance its comprehensibility. Materials and Methods: Twenty cases of TTD were included: 7 from Mexico and 14 from Spain. Clinical, microscopic, scanning electron microscopy (SEM) studies and X-ray microanalysis (XrMa) were carried out in all of them. Genetic studies were performed in all seven Mexican cases. Patients with xeroderma pigmentosum and xeroderma pigmentosum/TTD-complex were excluded. Results: Cuticular changes and longitudinal crests of the hair shaft were demonstrated. These crests were irregular, disorganized, following the hair longest axis. Hair shaft sulfur deficiency was disposed discontinuously and intermittently rather than uniformly. This severe decrease of sulfur contents was located close to the trichoschisis areas. Only five patients did not show related disturbances. Micro-dolichocephaly was observed in five cases and represented the most frequent facial dysmorphism found. It is also remarkable that all patients with urologic malformations also combined diverse neurologic disorders. Moreover, three Mexican sisters demonstrated the coexistence of scarce pubic vellus hair, developmental delay, onychodystrophy, and maxillar/mandibullar hypoplasia. Conclusions: TTD phenotype has greatly varied from very subtle forms to severe alterations such as neurologic abnormalities, blindness, lamellar ichthyosis and gonadal malformations. Herein, a multisystem study should be performed mandatorily in patients diagnosed with TTD.

Further insights in trichothiodistrophy: a clinical, microscopic, and ultrastructural study of 20 cases and literature review

Background: Trichothiodistrophy (TTD) is a rare autosomal recessive condition that is characterized by a specific congenital hair shaft dysplasia caused by deficiency of sulfur associated with a wide spectrum of multisystem abnormalities. In this article, we study clinical, microscopic, and ultrastructural findings of 20 patients with TTD with the aim to add further insights regarding to this rare condition. Additionally, analyses of our results are compared with those extracted from the literature in order to enhance its comprehensibility. Materials and Methods: Twenty cases of TTD were included: 7 from Mexico and 14 from Spain. Clinical, microscopic, scanning electron microscopy (SEM) studies and X-ray microanalysis (XrMa) were carried out in all of them. Genetic studies were performed in all seven Mexican cases. Patients with xeroderma pigmentosum and xeroderma pigmentosum/TTD-complex were excluded. Results: Cuticular changes and longitudinal crests of the hair shaft were demonstrated. These crests were irregular, disorganized, following the hair longest axis. Hair shaft sulfur deficiency was disposed discontinuously and intermittently rather than uniformly. This severe decrease of sulfur contents was located close to the trichoschisis areas. Only five patients did not show related disturbances. Micro-dolichocephaly was observed in five cases and represented the most frequent facial dysmorphism found. It is also remarkable that all patients with urologic malformations also combined diverse neurologic disorders. Moreover, three Mexican sisters demonstrated the coexistence of scarce pubic vellus hair, developmental delay, onychodystrophy, and maxillar/mandibullar hypoplasia. Conclusions: TTD phenotype has greatly varied from very subtle forms to severe alterations such as neurologic abnormalities, blindness, lamellar ichthyosis and gonadal malformations. Herein, a multisystem study should be performed mandatorily in patients diagnosed with TTD.

Aproximació al disseny de procediments i instruments per a la personalització de l'ensenyament a l'etapa primària des d'una perspectiva inclusiva

The main objective of this research is to found a new process about the personalization's curriculum for pupils with especial educational needs. In this research there are two objectives: the first objective is to describe a procedure for to do the individual planning for this pupils. This procedure is called "Procediment per cartes de personalització" (Pedragosa 2002). The other objective is centered to validate this procedure for teachers who are in active service in primary's etapa and to check if it's a good process for to do the individual planning in an inclusive approach. The procedure's cobcretion is about three basic referents: In the first, we consult with the current regulations, in the second we incorporate the inclusion's approach and the fundamentals of universal learning design, and finally we consult Ruiz's (1999) provides. We obtain the information for the research until, during and after of the formation's course (in 2003/2004). We introduced two questionnaire (until and after of formation sessions) and we register all of the sessions with a parlimentary report. About the main research results we can to affirm that the procedure is a good option for the professional's practice. It's an organized, ordered and coherent design with our curriculum. But, in spite of, we can to probate that there some interesting variables which are to influence to the procedure's efficiency.

Identificació de components inclusius en alguns centres escolars d'educació infantil i primària de la comarca d'Osona

The present essay –which is a pilot study conceived to continue the research in depth in the future- is based in a comparative analysis of educational practice between five different primary and pre-school teaching centres in Osona and the educational practice in inclusive educational centres. The essay introduces the objectives of the research and the theoretical and conceptual framework in which it is based (chapter 1) in relation with the main themes and expressions which are the purpose of the study: comprensivity, inclusive school and inclusive practice. The theoretical framework is linked to the principal regulations applied in our context. The study describes the instruments and procedure analysis describes the instruments and procedure analysis which have been designed and used for a qualitative methodological approach, together with the data obtained from the analysis of five teaching centres (chapter 2). The results from the research show that the practice done in the analised schools are not totally comparable to the ones in the inclusive environment. Notwithsanding, there are some similar points, although not totally coincident, like the fact that either the analysed schools or the ones with an inclusive approach show availability and interest in improving integration of all the pupils in the school, also the teachers work together in some aspects like, evaluation of pupils with special needs, objectives and contents and activities fort he specific kind of pupils with special needs parents and the majority of the analyzed schools, like those fallowing inclusive educational approaches, try the pupils with special needs to develop their acquisition within the ordinary class with adapted material. I think, these verifications, some of them close to inclusive educational practice, could constitute a starting point to analyse our model, in order to offer a common curriculum that could respect the different styles and rhythms of acquisition of all the pupils, so that promoting a more flexible and open schooling. In conclusion, the results of this analysis, although dues to its limits, they can not be generalized, they can help to find the necessary changes to bet for a qualitative education in a school for everyone.

Evolució i estabilitat d’àcids grassos i vitamines antioxidants a la llet materna

Recerca realitzada durant el periode Gener 2006-Abril 2007, a la Facultat de Farmàcia de la Universitat de Barcelona sota la direcció de la Dra. M. Carmen López Sabater. La nutrició durant els primers anys de vida té una enorme importància, amb repercussions en el creixement i desenvolupament del nen i en les possibles malalties futures. Tenint en compte que la llet materna és l’aliment ideal per al nadó durant els primers sis mesos de vida, és important conéixer la composició nutricional de la mateixa i la seva evolució al llarg de la lactància (calostre, llet de transició i madura). La llet conté nutrients majoritaris (proteïnes, carbohidrats i lípids) i nutrients minoritaris, com vitamines i minerals. S'ha desenvolupat i validat un mètode per a la determinació d'àcids grassos (AG) i Àcid Linoleic Conjugat (CLA) en llet materna per Cromatografia de Gasos "fast" (fast-GC), permetent reduir el temps d'anàlisi considerablement en comparació amb els mètodes utilitzats fins el moment. La repetibilitat i reproducibilitat trobades han estat bones, amb coeficients de variació inferiors al 10% en tots els casos. L'aplicació a 6 mostres de llet materna ha demostrat que es tracta d'un mètode senzill, ràpid, eficient i pràctic per a l'anàlisi rutinari d'un elevat nombre de mostres. També s'ha començat a desenvolupar un mètode per a l'anàlisi dels anàlegs de tocoferol de la llet materna, degut a l'interès de la vitamina E com a antioxidant natural. És un mètode per Cromatografia Líquida d'Ultra Resolució (UPLC) amb detecció per Fluorescència (FD) i per Photodiode Array (PDA) que permet treballar amb quantitats de mostra petites mantenint o inclús millorant la sensibilitat i reduint el temps d’anàlisi.

Memòria justificativa del treball realitzat durant l’estada a la Universitat de Wisconsin-Madison

Projecte de recerca elaborat a partir d’una estada a la Universitat de Wisconsin-Madison, EUA, Departament de Curriculum and Instruction, des de mitjans d’agost a mitjans de novembre de 2006. S’ha treballat en relació a la preparació de la tesi “Els grups interactius: una pràctica de les comunitats d’aprenentatge per a la inclusió de l’alumnat amb discapacitat “. La universitat de Wisconsin-Madison i en concret el departament de Curriculum and instruction compta amb professorat de reconegut prestigi internacional en l’àmbit de l’educació. Entre els temes que es treballen al departament i que vaig poder conèixer, en destaco les implicacions de l’educació en l’existència de desigualtats socials, així com les implicacions del govern i de les polítiques educatives en la creació i manteniment d’aquestes desigualtats, les reformes i polítiques educatives i el paper de l’educació en el més ampli context de la societat i les seves estructures, l’anàlisi del llenguatge vinculat amb les desigualtats i l’educació, la necessitat de tenir en compte la multiculturalitat des d’una perspectiva crítica, i les possibilitats de transformació en educació facilitades per les oportunitats d’interacció.

Funcions de les molècules associades a la mielina i la proteïna priònica cel•lular (PrPc) en neurodegeneració (Malaltia d’Alzheimer) i neuroinflamació (Esclerosi Múltiple)

Les proteïnes associades a la mielina (MAIS), Nogo-A, MAG i OMgp, són molècules que presenten una capacitat inhibitòria molt important per el recreixement axonal i la neuroreparació després de lesió. No obstant des de fa anys les seves funcions han estat ampliades i s’han involucrat en diferents processos degeneratius del sistema nerviós o en processos neuroinflamatoris del sistema nerviós central i el perifèric com ara l'Escleresi Múltiple (MS). La base neurobiològica d’indicadors moleculars que són responsables del dany axonal en MS segueixen sense estar plenament descrits. Recentment s’ha publicat que el mecanisme de senyalització Nogo-A pot regir els primers canvis de la desmielinització immunomediada del sistema nerviós central en el model animal de MS, l’encefalomielitis autoimmune experimental (EAE). De la mateixa forma la proteïna priònica cel•lular és una proteïna que s’ha associat majoritàriament a malalties espongiformes, però que recentment s’ha vinculat (no sense controvèrsia) amb la seva possible relació amb la Malaltia d'Alzheimer (AD), ja que seria capaç de reclutar els oligòmers d’Aβ (ADDLs), els quals correlacionen millor amb el grau de demència, i amb els que interacciona directament, actuant així com un possible mediador de la fosforilació de tau en la malaltia. No obstant, les funcions de les MAIS i de la PrPc en aquests models de la malaltia no estan clarament definits i, per altra banda, es desconeixen els mecanismes de senyalització implicats, no descartant de forma clara el component neural i l’immune.

Geología del Montgrí

This paper, fundamentally stratigraphic, is based on the vertical distribution of fauna in sediments which constitute the Montgri Massif. The stratigraphic series is composed of two units: one allochtonous (Mesozoic) and a second one autochtonous (Paleogene). The latter crops out in front of the thrust belt and presents the typical facies described by PALLI (1972). The allochtonous part is formed by the following units (from bottom to top): variegated gypsiferous shales of Keuper age; marls, limestones and dolomites from the Lias (Domerian); gray breccia ted dolomites: supraliassic; and Cretaceous limestones with rare interbeds of calcareous marls and nodular shaly marls. In this unit the Neocomian, Barremian (?), Aptian, Albian, Cenomanian, Turonian (?) and Santonian haven been recognized. Structurally, the Montgri Massif is part of a thrust belt which has been divided into three parts of different development ang age. Both parts are affected by ample synclinal folds of NE-SW directions and fractures of NW-SE orientation. The fractures condition the torrential streams as well as the karstic phenomena present in the Massif. These and the eolian actions are the main causes of the present geomorphology of the Montgri

Electroluminiscence and optical amplification in silicon nanostructures: towards the integration of electronics and photonics

This line of research of my group intends to establish a Silicon technological platform in the field of photonics allowing the development of a wide set of applications. Particularly, what is still lacking in Silicon Photonics is an efficient and integrable light source such an LED or laser. Nanocrystals in silicon oxide or nitride matrices have been recently demonstrated as competitive materials for both active components (electrically and optically driven light emitters and optical amplifiers) and passive ones (waveguides and modulators). The final goal is the achievement of a complete integration of electronic and optical functions in the same CMOS chip. The first part of this paper will introduce the structural and optical properties of LEDs fabricated from silicon nanostructures. The second will treat the interaction of such nanocrystals with rare-earth elements (Er), which lead to an efficient hybrid system emitting in the third window of optical fibers. I will present the fabrication and assessment of optical waveguide amplifiers at 1.54 ¿m for which we have been able to demonstrate recently optical gain in waveguides made from sputtered silicon suboxide materials.