Effect of sialic acid loss on dendritic cell maturation

Sialic acids are key structural determinants and contribute to the functionality of a number of immune cell receptors. Previously, we demonstrated that differentiation of human dendritic cells (DCs) is accompanied by an increased expression of sialylated cell surface structures, putatively through the activity of the ST3Gal.I and ST6Gal.I sialyltransferases. Furthermore, DC endocytosis was reduced upon removal of the cell surface sialic acid residues by neuraminidase. In the present work, we evaluate the contribution of the sialic acid modifications in DC maturation. We demonstrate that neuraminidase-treated human DCs have increased expression of major histocompatibility complex (MHC) and costimulatory molecules, increased gene expression of specific cytokines and induce a higher proliferative response of T lymphocytes. Together, the data suggest that clearance of cell surface sialic acids contributes to the development of a T helper type 1 proinflammatory response. This postulate is supported by mouse models, where elevated MHC class II and increased maturation of specific DC subsets were observed in DCs harvested from ST3Gal.I(-/-) and ST6Gal.I(-/-) mice. Moreover, important qualitative differences, particularly in the extent of reduced endocytosis and in the peripheral distribution of DC subsets, existed between the ST3Gal.I(-/-) and ST6Gal.I(-/-) strains. Together, the data strongly suggest not only a role of cell surface sialic acid modifications in maturation and functionality of DCs, but also that the sialic acid linkages created by different sialyltransferases are functionally distinct. Consequently, with particular relevance to DC-based therapies, cell surface sialylation, mediated by individual sialyltransferases, can influence the immunogenicity of DCs upon antigen loading.

La fin (l’infini) du bruit

Á... Á propos d’Erosphère propos d’Érosphère, dans un entretien pour la Revue LIEN2 en 1992, François Bayle explique que le projet d’une Suite fut déclenché par la composition de la 1ère œuvre du cycle – Tremblement de terre très doux. Il y indique : « je me suis petit à petit aperçu, en réalisant cette pièce, que j’y traitais d’un problème inhérent à l’acous- matique : celui du désir, [...] c’est-à-dire des sons appétissants, des sons voluptueux, ce qui m’a entraîné vers un projet plus vaste que j’ai appelé Érosphère, cette loi de gravitation du désir. »3 Plus tard le compositeur déclare : « Au moment d’Érosphère mon projet portait sur les mécanismes du désir, l’érotisme sonore, d’où le titre d’Éros- phère. Découvrir les archétypes érotiques des formes sonores. »4 Dans les notes qui accompagnaient la première édition en disque, Bayle présente sa définition du mot Érosphère : Ce tissu nerveux qui enveloppe notre monde habité d’un réseau d’ondes modulées à une infinité de fréquences, ce nuage de chaleur infra et supra sensorielle que diffusent des mégas milliards d’ émetteurs biologiques, cet anneau où circule la force de ce cosmos, je l’appelle l’érosphère.

Analysis of PAX2 gene alterations in renal cell tumors

Dissertation for applying to a Master’s Degree in Molecular Genetics and Biomedicine submitted to the Sciences and Technology Faculty of New University of Lisbon

Sudden sensorineural hearing loss : evaluation of co-morbidities and potential clinical associations

RESUMO: A surdez súbita (SS) caracteriza-se por uma perda abrupta de audição, mais frequentemente unilateral e associada a sensação de preenchimento aural, acufenos e vertigem. Afecta 5-20/100.000pessoas/ano (sobretudo adultos em fase activa na década de 40), com grande impacto na qualidade de vida. Possíveis causas incluem doenças infecciosas, circulatórias, traumáticas, imunológicas, neoplásicas, neurológicas, tóxicas e cocleares. No entanto, a causa da SS permanece desconhecida na maioria dos casos (80%), o que origina tratamentos controversos e frequentemente ineficientes. Os tratamentos disponíveis variam desde corticosteróides a antivirais, vasodilatadores, anti-agregantes, anticoagulantes, vitaminas e oxigénio hiperbárico (OHB). Atendendo a falta de informação relativa à etiologia e fisiopatologia da SS, pretendemos avaliar a evolução clínica dos doentes com SS tratados com OHB no Centro de Medicina Subaquática e Hiperbárica (CMSH) de Lisboa entre 2000 e 2005, durante um período mínimo de 5 anos, na tentativa de identificar eventuais factores de risco ou noxas clínicas com a SS. O estudo retrospectivo proposto baseia-se na revisão de processos clínicos do CMSH e na aplicação telefónica de questionários médicos de “follow-up” confidenciais – tanto a doentes (grupo de estudo), como aos respectivos esposos/companheiros/membros próximos da família (grupo de controlo) –, com particular ênfase nos antecedentes médicos e história clínica actual. Um estudo preliminar de 20 pessoas (10 doentes e 10 controlos) foi efectuado para antecipar dificuldades e estimar as necessidades logísticas. As dificuldades identificadas foram: 1) selecção dos doentes com números de telefone válidos e processos clínicos completos (com audiograma inicial e final); 2) contacto telefónico com os participantes de ambos os grupos (de estudo e controlo); 3) recursos humanos requeridos. Dado que a SS não é uma doença em si, mas um sintoma de uma doença subjacente, acreditamos que este estudo epidemiológico seja importante e útil, capaz de gerar novas luzes sobre a fisiopatologia e mecanismos desta entidade clínica.-------------ABSTRACT:Sudden sensorineural hearing loss (SSHL) is characterized by abrupt, mostly unilateral loss of hearing, frequently associated to aural fullness, tinnitus and vertigo. It affects 5-20/100.000 people/year (particularly working adults in the 40ths), with huge impact on quality of life. Possible causes include infectious, circulatory, traumatic, immunologic, metabolic, neoplastic, neurologic, toxic and unidentified cochlear diseases. Nevertheless, SSHL’s etiology remains unknown in most cases (80%), giving rise to controversial (and frequently ineffective) treatments. Available therapies range from corticosteroids to antivirals, vasodilators, antiaggregants, anticoagulants, vitamins and hyperbaric oxygen (HBO). Given the lack of data concerning SSHL’s etiology and physiopathology, we intend to evaluate clinical evolution of such patients treated with HBO in the Underwater and Hyperbaric Medical Center (UHMC) at Lisbon from 2000 to 2005 during a minimum period of 5 years, in an attempt to identify eventual risk factors or clinical associations to SSHL. The intended retrospective study is based on the review of patients’ medical charts from UHMC and confidential follow-up questionnaires applied telephonically both to patients (study group) and patients’ spouse/partner/close family member (control group), focusing past and present medical history. A preliminary study of 20 subjects (10 of each group) was performed to anticipate difficulties and to estimate the required logistics. The identified difficulties were: 1) selection of subjects with valid phone numbers and complete medical charts (with initial and final audiograms); 2) telephonic contact with subjects from the study and control group; 3) human logistics required. As it is believed that SSHL is not a disease by itself but rather a symptom of an underlying disease, we believe that this epidemiologic study is important and will hopefully generate sound scientific knowledge concerning physiopathology and mechanism of disease of SSHL.

Help-seeking for 'memory loss' by older adults in India : patient, caregiver and health providers' perspectives

ABSTRACT: Background. In India, prevalence rates of dementia and prodromal amnestic Mild Cognitive Impairment (MCI) are 3.1% and 4.3% respectively. Most Indians refer to the full spectrum of cognitive disorders simply as ‘memory loss.’ Barring prevention or cure, these conditions will rise rapidly with population aging. Evidence-based policies and practices can improve the lives of affected individuals and their caregivers, but will require timely and sustained uptake. Objectives. Framed by social cognitive theories of health behavior, this study explores the knowledge, attitudes and practices concerning cognitive impairment and related service use by older adults who screen positive for MCI, their primary caregivers, and health providers. Methods. I used the Montreal Cognitive Assessment to screen for cognitive impairment in memory camps in Mumbai. To achieve sampling diversity, I used maximum variation sampling. Ten adults aged 60+ who had no significant functional impairment but screened positive for MCI and their caregivers participated in separate focus groups. Four other such dyads and six doctors/ traditional healers completed in-depth interviews. Data were translated from Hindi or Marathi to English and analyzed in Atlas.ti using Framework Analysis. Findings. Knowledge and awareness of cognitive impairment and available resources were very low. Physicians attributed the condition to disease-induced pathology while lay persons blamed brain malfunction due to normal aging. Main attitudes were that this condition is not a disease, is not serious and/or is not treatable, and that it evokes stigma toward and among impaired persons, their families and providers. Low knowledge and poor attitudes impeded help-seeking. Conclusions. Cognitive disorders of aging will take a heavy toll on private lives and public resources in developing countries. Early detection, accurate diagnosis, systematic monitoring and quality care are needed to compress the period of morbidity and promote quality of life. Key stakeholders provide essential insights into how scientific and indigenous knowledge and sociocultural attitudes affect use and provision of resources.

The role of Hedgehog signaling during zebrafish larvae fin fold regeneration

Several studies have demonstrated that although the structure of the adult and larval zebrafish caudal fin is different, there are similarities at the cellular and molecular level that turn larval zebrafish fin fold a useful model to study the basic principles of regeneration. In this process, while the essential role for Hedgehog (Hh) signaling is well established in the adult zebrafish caudal fin system, its involvement in juvenile tissue regeneration is still unknown. The aim of this Master thesis was therefore to evaluate the contribution of the Hh signaling pathway to the larval zebrafish fin fold regeneration process. Accordingly, we analyzed the expression of several Hh signaling components through in situ hybridization. Here, we showed that several of these genes are effectively expressed in the larval regenerating fin tissue, suggesting a role for Hh signaling also during larval regeneration. However, divergence in the regulation of few Hh signaling components appears to exist between the adult and larval zebrafish fin regeneration processes. Nevertheless, similarly to adult caudal fin regeneration, when Hh signaling was blocked, by using cyclopamine, the larval fin fold regenerative outgrowth is severely impaired. Since larval zebrafish fin fold is ciliated, and primary cilia are closely related to Hh signaling regulation in vertebrate systems, we further addressed the role of primary cilia during larval fin fold regeneration process. To this end, we used the zebrafish iguana mutant, in which primary cilia are not formed, to study the modulation of Hh signaling expression during larval fin fold regeneration in the absence of primary cilia. Here, we found that several genes were expressed with a delay, coincident with the delay in the mutant fin fold regeneration observed in previous work. We show that Hh signaling in the fin fold is crucial to promote cell proliferation. When Hh signaling is blocked using cyclopamine there is a strong blockage of cell proliferation and regeneration is also blocked. Surprisingly, in iguana mutants where Hh signaling is impaired but not totally blocked, cell proliferation is not detected but regeneration still occurs. This raises the question about the requirement of cell proliferation in larvae fin fold regeneration. By blocking the cell cycle using aphidicolin we demonstrate that cell proliferation is not necessary for zebrafish larvae fin fold regeneration.