Le récepteur du mannose-6-phosphate cation indépendant (RM6P-CI) permet l'endocytose puis le transfert de molécules porteuses du marqueur M6P vers les lysosomes. Pour améliorer à la fois l'affinité pour le RM6P-CI et la stabilité du résidu M6P, nous avons procédé à la synthèse d'analogues isostères stables et fonctionnalisés en position anomère pour permettre un couplage efficace à des molécules d'intérêt thérapeutique. Tout d'abord un couplage à des enzymes recombinantes humaines a été réalisé. Le remodelage de la partie oligosaccharidique de l'enzyme lysosomale GAA, dont la déficience est responsable de la maladie de Pompe, a permis de mettre en évidence que la néoglycoGAA est reconnue efficacement par les RM6P-CI et que son activité enzymatique est totalement conservée. Deuxièmement, le couplage de ces analogues du M6P à des porphyrines en vue de la thérapie photodynamique des cancers est envisagé. Le modèle mis au point en série du mannose a permis de valider notre approche de ligation de saccharides à des photosensibilisateurs par des méthodes évitant après couplage les étapes classiques de déprotection des saccharides. L'étude biologique menée sur les porphyrines glycosylées préparées a démontré leur cytotoxicité photoinduite. / The cation independent mannose-6-phosphate receptor (CI-M6PR) allows the endocytosis and the transfer of molecules bearing the M6P marker to lysosomes. To improve both the affinity for the CI-M6PR and stability of the M6P residue, we carried out the synthesis of isosteric M6P analogues functionalized at the anomeric position to allow efficient coupling to molecules of therapeutic interest. First, the coupling on human recombinant enzymes was performed. The remodelling of the oligosaccharide part of the lysosomal enzyme GAA, whose deficiency is responsible for Pompe disease, helped to highlight the neoglycoGAA is recognized efficiently by CI-M6PR and its enzymatic activity is completely preserved. Second, the coupling of these analogues of M6P to porphyrins for photodynamic therapy of cancer was considered. The model developed in the mannose series has validated our strategy of ligation of saccharides to photosensitizers. The employed methods avoid the conventional steps of deprotection of saccharides after coupling. The biological study with the prepared glycosylporphyrins demonstrated the photoinduced cytotoxicity.

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Introduction to the issue: Stay in an intensive care unit or anaesthesiology and resuscitation department has a demonstrable effect on the quality of life, whether mental, physical, or mental. A large percentage of patients experience post intensive care syndrome. The huge challenge for nursing care is to reduce this percentage and enable patients to recover in the best possible way and return to normal life of the same quality as before the hospitalization Methodology: The aim of this work is to find out how the quality of life of patients is affected after hospitalization in the intensive care unit or anaesthesiology and resuscitation department, with a proportion of acute renal failure and the need for continuous renal replacement. First, patients were evaluated with APACHE II score, SOFA and TISS 2. Next, questionnaires in which they responded to the period before hospitalization (SF 36, DEMMI, ADL, IADL) were filled, when released from ARO they went through the test of physical capability, (30s sit-up test, 6-minute walk test), further measurements when released from ICU took place (HADS, MAF, DEMMI, ADL, 30s sit-p test, 6-minute walk test), and after three months (SF 36, HADS, MAF, DEMMI, IADL, ADL 30s sit-up test, 6-minute walk test and a week of wearing a Garmin vivofit bracelet). Main...

Individuals born with primary immune deficiency diseases (PIDD) have a dysfunctional immune system, and many are treated by lifelong injections of immunoglobulin therapy. Studies have shown that these patients have low health-related quality of life (HRQOL) and well-being (WB) and that these outcomes might be improved by the availability of therapy innovated according to preferences for fewer needle sticks or a shorter infusion time. Regulators at the U.S. Food and Drug Administration (FDA) have approved therapies innovated per these preferences. However, there is limited data demonstrating how these innovations impact HRQOL and WB. Using the biopsychosocial model, the purpose of this cross sectional quantitative study was to evaluate whether patients with PIDD using therapies innovated for fewer needle sticks or a shorter infusion time had a higher mean HRQOL and WB compared to those who were not. The study included 153 patients who completed the Patient Reported Outcomes Measurement Information System (PROMIS)-29 survey. The dependent variables were HRQOL and WB measured by PROMIS-29, and the independent variables were the medical product innovations. Independent samples t tests results showed mean PROMIS-29 scores were not statistically different (p > .05). This suggests patients were optimized according to their treatment preference. A subgroup of patients who had taken the PROMIS-29 survey more than once concurrent with switching to a therapy aligned with patient preferences showed improved HRQOL and WB. These findings have implications for positive social change in that seeking the patient's voice to inform medical product innovation and FDA regulatory decision-making has potential to improve biopsychosocial outcomes.

Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME), Farber Lipogranulomatosis (FL), and a rare variant form of Neonatal Progeroid Syndrome (NPS) are three monogenetic rare disorders caused by pathogenic variation in genes encoding lipid modifying proteins. FL and SMA-PME are caused by loss of function mutations in ASAH1, encoding the acid ceramidase (aCDase) enzyme. It is not, however, known how aCDase deficiency can produce either the isolated neurological symptoms of SMA-PME or the predominantly systemic symptoms of FL. Further, a recently identified variant form of NPS has been attributed to variants in ANO6, encoding a dual function calcium-activated chloride channel and glycerophosphoserine (GPS) scramblase. Here, it is not known how ANO6 mutation causes the premature aging phenotype that defines NPS. To address these questions, I sought to elucidate pathogenic changes in lipid metabolism that associate clinical phenotype. I show here that the different patient mutations in ANO6 cause a non-physiological gain of channel function and either a loss or gain of scramblase function depending on the variant expressed. Both variants, however, alter GPS metabolic homeostasis suggesting a common mechanism of action. To provide in vivo insight, I characterized a novel mouse model based on our NPS patient genetics, showing extremely low penetrance of disease symptoms in terms of live births yet confirming that affected animals show impaired GPS metabolism in affected organs. Next, I characterized the clinical presentation of six new patients with SMA-PME and identified distinct sphingolipid metabolic fingerprints in FL and SMA-PME cells. I show that FL is defined by a hypometabolic sphingolipid phenotype with cellular and molecular features of a classic lysosomal storage disorder. By contrast, SMA-PME has a hypermetabolic sphingolipid phenotype with features of non-classic lysosomal trafficking disorders. To provide clinical insight, I assessed the potential of enzyme replacement therapy, demonstrating a rescue of sphingolipid metabolism in SMA-PME patient cells. Together, this thesis identified changes in the cellular and tissue lipid profiles of patients with ANO6-NPS, SMA-PME, or FL, elucidating some of the lipid-centric pathomechanisms of these diseases.

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Introduction : La mortalité associée à l’insuffisance rénale aiguë (acute kidney injury ‘’AKI’’) aux soins intensifs pédiatriques (SIP) dépasse les 50%. Des études antérieures sur la thérapie de remplacement rénal (TRR) ont fait ressortir plusieurs facteurs de risque de mortalité dont le syndrome de défaillance multiviscérale (SDMV) et la surcharge liquidienne ≥ 10 à 20% avant l’initiation de la TRR. L’objectif de cette étude était d’identifier les principaux facteurs de risque de mortalité à 28 jours après l’initiation de la TRR chez les patients atteints d’AKI aux SIP. Méthode : Il s’agit d’une étude de cohorte rétrospective aux SIP d’un centre tertiaire. Tous les enfants ayant reçus de la TRR continue ou de l’hémodialyse intermittente pour AKI, entre janvier 1998 et décembre 2014, ont été inclus. Les facteurs de risque de mortalité ont été préalablement identifiés par quatre intensivistes et deux néphrologues pédiatres et analysés à l’aide d’une régression logistique multivariée. Résultats : Quatre-vingt-dix patients ont été inclus. L’âge médian était de 9 [2-14] ans. La principale indication d’initiation de la TRR était la surcharge liquidienne (64,2%). La durée médiane d’hospitalisation aux SIP était de 18,5 [8,0-31,0] jours. Quarante patients (44,4%) sont décédés dans les 28 jours suivant l’initiation de la TRR et quarante-cinq (50,0%) avant la sortie des SIP. Le score de PELOD ≥ 20 (OR 4,66 ; 95%CI 1,68-12,92) et la surcharge liquidienne ≥ 15% (OR 9,31; 95%CI 2,16-40,11) à l’initiation de la TRR étaient associés de façon indépendante à la mortalité. Conclusion : Cette étude a permis de faire ressortir deux facteurs de risque de mortalité à 28 jours à l’initiation de la TRR : la surcharge liquidienne et la sévérité du SDMV mesurée par le score de PELOD. / Introduction: Mortality rate associated with acute kidney injury (AKI) in pediatric intensive care units (PICU) exceeds 50%. Prior studies on renal replacement therapy (RRT) have highlighted different mortality risk factors including the presence of a multiple organ dysfunction syndrome (MODS) and fluid overload ≥ 10 to 20% before starting RRT. The aim of this study was to identify most important risk factors of 28-day mortality in patients with AKI at RRT initiation in PICU. Methods: We conducted a retrospective cohort study in a tertiary care pediatric center. All critically ill children who underwent acute continuous RRT or intermittent hemodialysis for AKI between January 1998 and December 2014 were included. A case report form was developed and specific risk factors were identified by a panel of four pediatric intensivists and two nephrologists. Risk factors analysis was made using logistic regression in SPSS and SAS software. Results: Ninety patients were included. The median age was 9 [2-14] years. The most common indication for RRT initiation was fluid overload (FO) (64.2%). The median PICU length of stay was 18.5 [8.0-31.0] days. Forty of the 90 patients (44.4%) died within 28 days after RRT initiation and forty-five (50.0%) died before PICU discharge. In a multivariate logistic regression analysis, a PELOD score ≥ 20 (OR 4.66; 95%CI 1.68-12.92) and percentage of FO ≥ 15% (OR 9.31; 95%CI 2.16-40.11) at RRT initiation were independently associated with mortality. Conclusion: This study suggests that fluid overload and severity of MODS measured by PELOD score are two risk factors of 28-day mortality in PICU patients on RRT.

A perimenopausa é a fase da vida reprodutiva feminina caracterizada diversas alterações, inclusive cognitivas devido ao hipoestrogenismo. Através de estudo duplo-cego randomizado com 16 mulheres na perimenopausa deprimidas que receberam estradiol e 16 que receberam placebo analisou-se as alterações cognitivas da atenção, memória e linguagem; o efeito da reposição hormonal com estradiol e a correlação entre os sintomas depressivos e menopausais com as alterações destas funções. Os resultados mostraram: melhora do controle inibitório, memória imediata e tardia (verbal e visual) e da capacidade de nomeação nos dois grupos; melhora dos sintomas depressivos e menopausais para o grupo que recebeu reposição hormonal: e não correlação entre a melhora destes sintomas e a melhora das funções cognitivas / Perimenopause is the female reproductive life period characterized by several changes including cognitive impairments related to hypoestrogenism. In a randomized double-blind study 16 depressive perimenopaused women took estradiol, while another group of 16 depressive perimenopaused women took placebo. Cognitive alterations associated to attention, memory and language, and estradiol hormone replacement therapy effects were evaluated. In addition, correlations among symptoms of depression and menopause, and cognitive alterations were also analyzed. The results had shown, in both groups, an improvement in inhibitory mental control, in immediate and delayed (verbal and visual) memory, and in naming capacity. In the group that received hormone replacement therapy our findings revealed a weakening of depression and menopause symptoms, which had shown no correlation with cognitive functions

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Made available in DSpace on 2014-08-26T17:31:46Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 69585.pdf: 1181357 bytes, checksum: 50462d1ba789c7b199ee8460ca90f3b8 (MD5) / Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil / A Doença de Gaucher (DG) é uma Doença de Depósito Lisossômico (DDL) e seu tratamento baseia - se na terapia de reposição enzimática. Tal terapia foi um marco na vida de pacientes e especialistas, pois mudou a história da evolução da doença, caracterizando um a nova era na Genética Médica. Este trabalho tem como objeto de pesquisa as perspectivas trazidas por profissionais, com experiência em trata r a Doença de Gaucher no Sistema Único de Saúde no estado do Rio de Janeiro. Uma vez que a DG é a única condição d o grupo das DDL a ser contemplada por uma Política Ministerial, promovendo acesso a drogas de alto custo através de um Protocolo Clínico e Diretrizes Terapêuticas (PCDT). O o bjetivo geral foi a nalisar a prática da aplicação do protocolo oficial de tratame nto da DG e o seu entendimento a partir da ótica dos médicos tratadores, profissionais de saúde e gestores do Centro de Referência , o Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO). Os objetivos específicos foram primeiramente id entificar a formaçã o profissional dos envolvidos no programa, analisar a ótica desses profissionais sob re as recomendações do PCDT e como estes situam o Centro de Referência (CR) e m seu atual funcionamento , e d iscutir de maneira crítica a visão dos profiss i onais a respeito dos benefícios e de possíveis falhas do programa. Foram realizadas entrevistas temáticas semiestruturadas e a elas aplicou - se a análise de conteúdo. No que tange ao entendimento sobre o PCDT - DG e o seu viii funcionamento, os resultados apontam a importância da existência de um balizador, um programa robusto governamental, revisado por especialistas bem capacitados no tema. O PCDT - DG foi um avanço na saúde, oficializando e garantindo o acesso à medicação de maneira embasada, controlada por câmar as técnicas estaduais, permitindo a efetuação de pregões públicos, uma maneira transparente de aquisiçã o de drogas de alto custo comparada a medidas judiciais . Os sujeitos da pesquisa são favoráveis ao programa, no entanto possuem uma abordagem crítica ao sistema de saúde no que diz respeit o a entraves na rede de assistência cirúrgica e de reabilitação. Um grande gargalo atualmente no SUS não é exclusivo ao programa da DG: certos questionamentos éticos na fomentação do diagnóstico laboratorial por parte da indústria farmacêutica, apesar de haver relações amigáveis entre esses dois atores no CR. Concluímos que muitos avanços foram conquistados a partir da implementação do protocolo e que talvez este possa servir como modelo para garantir acesso ao tratamento de outras DDL. Algumas incongruências do siste ma são questionáveis e discutida s entre gestores, médicos e usuários, entretanto ainda são muito poucos os estudos publicados no Brasil sobre o tema . / Gaucher disease (GD) is a Lysosomal Storage Disease (LSD) and its treatment is based on enzyme replacement therapy. Such therapy was a milestone in patients `s lives and experts in the field, changing the disease natural history . This work aims at present ing the treatment of GD in the Unified Health System i n the state of Rio de Janeiro, as it is the only LSD to be covered by a Ministerial policy , which promotes access to high cost drugs through a Clinical Gui deline (CG) . The overall objective was to analyze the practical application of the CG protocol in the treatment of GD, and how this guideline was interpreted and used by the medical c haracters , health professionals and ma nagers of the Reference Center and the State Institute of Hematology Arthur de Siquei ra Cavalcanti (HEMORIO ). The specific objectives were to identify the training of those involved in the program, to analyze how professionals viewed the recommendations included in the CP, what they thought about the Reference Center for GD and to critical ly discuss the benefits and possi ble shortcomings of the program . Thematic semi - structured interviews were conducted, and the content analysis was applied. Regarding the understanding of the CP - GD and its op eration, the results point the importance of t he existence of a robust government program, reviewed by well - trained experts in the subject. The CP - GD was a health`s breakthrough , ensuring access to medication, controlled by state technical chambers, a llowing the practice of public auctions, a transpar ent way of purchasing high - cost drugs when compared to individual litigation. The steakeholder`s research were x favo rable to the program, although they criticized the health network constraints for specialized care, such as surgical services and rehabilitat ion. Another major bottleneck in the health system, not exclusive for G D is ethical issues regarding laboratory diagnosis by the pharmaceutical industry. We conclude d that many advances have been achieved from the implementation of the CP, and that hopeful ly this can serve as a model to ensure access t o treatment for other LSD. Managers, physicians and users point out some inconsistencies in the system although there is still limited published data on this subject in Brazil.