Дисертації з теми "Gauchers disease"
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Shebani, Eyman. "Ultrastructural Studies of the Airway Epithelium in Airway Diseases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6632.
Повний текст джерелаMonlleó, Mas Ester. "Aminocyclitol and iminosugar derivatives related to Gauche disease." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/400871.
Повний текст джерелаLa malaltia de Gaucher és una de les malalties d’emmagatzematge lisosomal més freqüent. Una mutació al gen gba1 provoca un incorrecte plegament de l’enzim Glucocerebrosidasa (GCase) que impedeix el seu transport del reticle endoplasmàtic (ER) fins al lisosoma, on té lloc la hidròlisi de la glucosilceramida (GluCer). Això provoca una acumulació d’aquest substrat, originant els símptomes clínics. En aquesta tesi s’ha sintetitzat una petita col·lecció de compostos per tal estudiar la influència del pKa de diferents inhibidors en la seva potencial activitat chaperona, és a dir, estudiar la seva capacitat de unir-se a la GCase mal plegada del reticle per facilitar-ne el correcte plegament i permetre el seu transport cap a lisosoma. Per aquest motiu, es buscaven compostos que presentessin una alta afinitat per la GCase en les condicions neutres del reticle endoplasmàtic, però que tinguessin baixa afinitat per aquest enzim a pHs lleugerament àcids com el del lisosoma (pH 5.2), per tal que no bloquegés l’activitat hidrolasa d’aquest enzim al lisosoma. Desprès d’analitzar els compostos amb diferents assajos, es va posar de manifest la importància de les condicions d’assaig a l’hora d’estudiar la inhibició d’un enzim, ja que diferents assajos poden conduir a conclusions diferents. Malgrat que no es va poder establir cap correlació directa entre el pKa dels inhibidors i la diferència d’activitat segons el pH de l’assaig, es va descobrir un dels derivats de DNJ amb millor potència inhibitòria de imiglucerasa (Gcase recombinant) descrit fins el moment. Per altra banda, es va analitzar la capacitat d’inhibició de GCS dels compostos sintetitzats, descobrint-se alguns inhibidors d’aquest enzim més potents que la NB-DNJ, compost que s’utilitza actualment com a inhibidor de GCS per al tractament de la malaltia de Gaucher, i possible comportament dual (inhibidors de GCS i chaperones per GCase).
Thomas, A. S. B. "Vascular events in Fabry and Gaucher disease." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1433363/.
Повний текст джерелаMassaro, Giulia. "Intravenously administered gene therapy for neuronopathic Gaucher disease." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10042055/.
Повний текст джерелаAitchison, K. L. "Lentiviral vectors for gene therapy of Gaucher disease." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1465062/.
Повний текст джерелаWillemsen, Robert. "Gaucher disease an immunoelectron microscopic and biochemical study /." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 1995. http://hdl.handle.net/1765/13738.
Повний текст джерелаDavies, E. H. "Developing markers of neurological manifestations in Neuronopathic Gaucher Disease." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1310245/.
Повний текст джерелаWei, Chao. "Molecular analysis and expression of the human glucocerebrosidase gene." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq36653.pdf.
Повний текст джерелаSmith, Nicholas James Chapman. "Neuronopathic Gaucher disease : the pathobiological effects of glucosylsphingosine upon cellular actin within the central nervous system." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648776.
Повний текст джерелаMADEO, ANNALISA. "Defective FAS-Mediated Apoptosis and Immune Dysregulation in Gaucher Disease." Doctoral thesis, Università degli studi di Genova, 2021. http://hdl.handle.net/11567/1046904.
Повний текст джерелаBACKGROUND: Gaucher disease (GD) is a rare disorder characterized by defective function of b-glucocerebrosidase, which leads to progressive accumulation of its substrate in various organs, particularly the mononuclear phagocyte system. Hepatosplenomegaly and cytopenia represent the disease’s most common features, but patients with GD also show hyperinflammation, hypergammaglobulinemia, and immune dysregulation involving B, T, and natural killer cells. As clinical phenotype can be underhand, symptoms can overlap with autoimmune lymphoproliferative syndrome (ALPS) or other ALPS-like disorders. OBJECTIVE: To evaluate the ALPS-like immunological pattern and apoptosis function in patients with GD. METHODS: We evaluated lymphocyte subsets and immunophenotypic and serological features of ALPS (double negative T cells [DNTs], B220DDNTs, CD27D, T-reg/HLADR ratio, IL-10, IL-18, vitamin B12) in a population of patients with GD. Moreover, we tested FAS/TRAIL-induced apoptosis and CASP8/CASP10/PARP function in patients showing an immune-dysregulation pattern. RESULTS: A total of 41 patients (33 treated, 8 treatment-naïve) were studied. Nine (21%) and 7 (17%) of 41 patients had high DNT and B220DDNT counts, respectively. Overall, 10 of 41(24%) patients showed immunological features suggestive of ALPS that were more frequent in treatment-naïve subjects (P [ .040 vs P [ .031) and in those with early onset of the disease (P [ .046 vs P [ .011), respectively. FAS-induced apoptosis and caspase activation were further evaluated in these 10 patients and were found to be defective in 7 of them. CONCLUSIONS: We show that patients with GD may have ALPS-like features and FAS-mediated apoptosis defects that are more pronounced in treatment-naïve subjects and in patients with early onset of the disease. Therefore, diagnostic workup of patients with an ALPS-like phenotype should include screening for GD.
Orwig, Susan D. "Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/45816.
Повний текст джерелаRoos, Jonathan Carl Pontus. "Studies on the molecular pathogenesis of the sphingolipid storage disorders, with particular reference to Gaucher's disease." Thesis, University of Cambridge, 2013. https://www.repository.cam.ac.uk/handle/1810/283914.
Повний текст джерелаSerra, Vinardell Jenny. "Generació d'un model cel·lular osteoblàstic i aproximacions terapèutiques per a la malaltia de Gaucher." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/328708.
Повний текст джерелаGaucher disease (GD) is the most prevalent lysosomal storage disorder and in most cases is caused by mutations in the GBA1 gene, which encodes the enzyme glucocerebrosidase (GBA1). This protein mainly hydrolyzes the sphingolipid glucosylceramide (GlcCer) into glucose and ceramide. Gaucher patients have a deficient GBA1 enzyme activity which causes that GlcCer accumulates in lysosomes of macrophages forming the so-called "Gaucher cells". GD is an autosomal recessive disorder and can be classified in three clinical subtypes, depending on the presence and degree of neurological manifestations: type 1 (GD1, no neuronopathic), type 2 (GD2; acute neuronopathic) and type 3 (GD3; subacute neuronopathic). The GD1 is characterized by visceral, haematological and bone manifestations. The pathological mechanisms of bone alterations in GD are still poorly understood. But it seems that Gaucher cells, immunitary system and bone cells play an important role. Of the current therapeutic approaches for treatment of the disease, enzyme replacement therapy (ERT) is the most commonly used. However, in the last 10 years pharmacological chaperones therapy has become an attractive option to improve the folding and transport of some mutated enzymes. The aim of this work has been the identification and characterization of compounds with positive effect on the activity of some mutant glucocerebrosidases to act as chaperones. Also, a model of mesenchymal and osteoblastic GD1 has been generated. In this model is being assessed the involvement of deficient GBA1 activity in the osteoblast differentiation process and, indirectly, in the capacity of osteoclasts formation.
La enfermedad de Gaucher (GD) forma parte de un conjunto de enfermedades que reciben el nombre de "enfermedades de acumulo lisosómico". La GD es la más prevalente y en la mayoría de los casos es debida a mutaciones en el gen GBA1 que codifica la enzima glucocerebrosidasa (GBA1) la cual hidroliza, principalmente el esfingolípido glucosilceramida (GlcCer) en glucosa y ceramida. En la GD ésta enzima presenta una actividad deficiente y la GlcCer se acumula en los lisosomas de los macrófagos formando las células Gaucher. La GD es una patología autosómica recesiva e incluye 3 subtipos clínicos, en función de la presencia y el grado de las manifestaciones neurológicas: tipo 1 (GD1; no neurológica), tipo 2 (GD2; neurológica aguda), y tipo 3 (GD3; neurológica subaguda). La GD1 se caracteriza por presentar problemas viscerales, hematológicos y óseos. La patofisiología de las manifestaciones óseas de la GD1 es poco conocida pero parece ser que las células Gaucher, el sistema inmunológico y las células óseas juegan un papel importante. De todas las aproximaciones terapéuticas para el tratamiento de la GD, la terapia de substitución enzimática (ERT) es la más habitual, pero en los últimos 10 años la terapia con chaperones farmacológicas ha resultado ser una buena opción para mejorar el plegamiento y el transporte de aquellos enzimas mutados que lo requieren. El trabajo que se presenta en ésta tesis doctoral ha permitido identificar algunos productos que presentan una buena capacidad de aumentar la actividad de algunas glucerebrosidasas mutadas y actuar por lo tanto como chaperonas farmacológicas. Además, se ha elaborado un modelo mesenquimal y osteoblástico de la GD1 en el que se está evaluando la implicación de la deficiente actividad de la enzima GBA1 en la diferenciación osteoblástica y, indirectamente, en la activación de la formación de los osteoclastos.
Moran, Mary Teresa. "Gaucher's disease : differential gene expression in the understanding of its pathogenesis." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621720.
Повний текст джерелаLorenzo, Vivas Erica. "lnduced Pluripotent Stem cells disease modeling: approaching Gaucher and Tay Sachs." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/128928.
Повний текст джерелаLas iPS (células pluripotentes inducidas) se han revelado como potentes herramientas en la creación de modelos de enfermedades humanas para su estudio y el testeo de potenciales drogas. En este marco hemos desarrollado un proyecto para derivar iPS de fibroblastos de pacientes de Gaucher y Tay Sachs, ambas enfermedades monogénicas recesivas. La enfermedad de Gaucher se caracteriza por la deficiencia de la glucocerebrosidasa (GBA), lo que conlleva la acumulación de su substrato, la glucosilceramida, en macrófagos y neuronas. Esta enfermedad tiene tres presentaciones I, que es sistémica; II, que es una forma neuronopática aguda, tiene efectos fatales ya que los pacientes rara vez sobreviven a los dos años de edad; y III, que es una mezcla de las dos anteriores, siendo neuronopática crónica, sin llegar a la severidad del tipo II. Tay Sachs es una enfermedad que se caracteriza por la deficiencia de la Hexosaminidasa A (HexA) lo que conlleva el almacenamiento en el lisosoma del gangliósido GM2. Los pacientes de esta enfermedad presentan daños neurológicos, provocando la muerte en la mayoría de los casos. En este proyecto se han desarrollado las iPS derivadas de fibroblastos de un paciente de Gaucher tipo II, y de otro de Tay Sachs. Las iPS resultantes de ambas enfermedades han sido caracterizadas para constatar su estado pluripotente y diferenciadas a neuronas para comprobar que presentan el fenotipo característico de las enfermedades. En el caso de Gaucher, mediante ensayos enzimáticos y detección de la GBA1 por western blot, detectando una menor actividad en las neuronas gaucher que en las WT, lo que es consecuente con la menor cantidad de GBA1 detectada. En el caso de Tay Sachs, las neuronas se han analizado mediante inmunohistoquímica, marcando Lamp2, típico de lisosomas y se ha observado un aumento de tamaño y cantidad respecto de las células WT diferenciadas en paralelo. También han sido analizadas por microscopía electrónica, presentando una acumulación de cuerpos laminares en los lisosomas y aumento de número y tamaño de éstos. Ambas enfermedades han sido utilizadas como modelos para probar compuestos en las neuronas derivadas de las iPS derivadas de fibroblastos del paciente y comprobar su eficacia.
Mahan, Farrah R. B. A. "Pain and Fatigue Associated with Generalized Joint Hypermobility in Gaucher Disease." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1525168102345918.
Повний текст джерелаSinclair, Graham Bernard. "Mutation analysis, heterologous expression, and characterization of human glucocerebrosidase." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ62529.pdf.
Повний текст джерелаLidchi, Victoria Gabrielle. "A portfolio." Thesis, University of Surrey, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267366.
Повний текст джерелаSpitz, Mariana. "Mutações da glicocerebrosidade em pacientes com doença de Parkinson." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-05022007-123329/.
Повний текст джерелаIntroduction: Parkinson\'s disease is a neurodegenerative disorder due to the loss of dopaminergic neurons in the substantia nigra, primarily, and in other brain regions. It is clinically characterized by tremor, rigidity, bradykinesia and postural instability. Treatment is symptomatic and consists essentially in replacing the deficient dopamine. The etiology of Parkinson\'s disease remains unknown, but recent advances in Neurology have provided data concerning the pathophysiological mechanisms involved. Mithocondrial dysfunction, oxidative stress and protein degradation are some of the cellular processes that have been linked to dopaminergic neurons degeneration. The field of genetics in Parkinson\'s disease has gained special attention in the past decade, thanks to the discovery of several genes associated with the development of the disease. A recently described genetic risk factor for Parkinson\'s disease is the presence of glucocerebrosidase gene mutations. Glucocerebrosidase is a lysosomal enzyme which is deficient in Gaucher disease. Although most studies published to date have confirmed such association, a recent article from Norway could not find statistical significance when Parkinson\'s disease patients were analyzed for glucocerebrosidase mutations, generating controversy. Objective: To search for glucocerebrosidase mutations in Parkinson\'s disease patients in Brazil, followed at the Movement Disorders Division at Hospital das Clínicas, University of São Paulo Medical School, and correlate these findings with recently published studies which evaluated this association in other populations worldwide, besides describing possible features of patients carrying the mutations that may help differentiating them from non-carriers. Methods: Sixty five patients diagnosed with Parkinsons disease, with disease onset before age 55, and 267 age and sex-matched controls were included in the study. DNA analysis of the three most common glucocerebrosidase mutations in the Brazilian population, N370S, L444P and G377S, was performed utilizing samples obtained from mouth mucus. Results: Glucocerebrosidase gene mutations were identified in two of the 65 Parkinson\'s disease patients and in none of the 267 controls. The two patients who were carriers of mutations (one of them had L444P and the other L444P+E326K) had a clinical picture indistinguishable from the other Parkinson\'s disease non-carriers patients. Conclusion: A statistically significant association (P=0,0379, Fisher\'s exact test) between Parkinson\'s disease and glucocerebrosidase mutations was observed in our population. The prevalence of glucocerebrosidase mutations was higher than expected for the general population, though lower than reported in previous international studies. It is expected that the finding of this association will allow a better understanding of Parkinson\'s disease mechanisms and that in a near future it may help providing the development of new therapeutic strategies.
Rozenberg, Roberto. ""Análise molecular das doenças de Gaucher e Tay-Sachs no Brasil"." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/41/41131/tde-27092006-154138/.
Повний текст джерелаThis study describes the molecular diagnosis of Gaucher (GD) and Tay-Sachs disease (TSD) patients in Brazil. Nine cases of the classic infantile form of TSD were analyzed disclosing a prevalence of the IVS7+1g>c mutation, described previously in Portuguese patients. Ten cases of juvenile and late-onset TSD forms were diagnosed showing genetic heterogeneity. Among the B1 variant cases, there was a predomenance of mutation R178H that was also associated to Portuguese ancestry. The presence of the same mutations in Brazilian and Portuguese cases are probably due to common ancestry. A family with 4 affected patients of late onset TSD showed and extensive intrafamilial clinical variability, highlighting relevant characteristics of diagnosis and implications of heterozygote screening programs. Among 263 GD patients, the detection of nine mutations by RFLP revealed 76% of the mutant alleles and a preponderance of N370S and L444P, similar to other populations. The type 3 neuronopathic patients presented a high frequency of mutation G377S, that is also described among Portuguese cases. The patients with G377S indicated the possibility of an allele dose effect for this mutation. Recombinant alleles, presenting pseudogene mutations were detected at a high frequency. Several genotype-phenotype correlations could be verified, highlighting a low penetrance of genotype N370S/N370S and corroborating the importance of molecular diagnosis in GD cases, due to its predictive value. The search for rare mutations at the GBA gene, using dHPLC and DNA sequencing after RFLP analysis, allowed the detection of 84% of the alleles among 54 patients. Fourteen new GD causing mutations were described. Several genotype-phenotype correlations could be established, confering prective value to the identification of these mutations. Finally, the study of the association of GD and Parkinson disease (PD) lead to the detection of a significant increase in the frequency of GBA mutations carriers, among 65 PD patients (2/65=3%) with earlier disease onset compared to a control group (n=267 individuals). This work confers further evidence for the fact that GBA mutations are a rare but consistent risk factor for PD.
Uemura, Norihito. "Viable neuronopathic Gaucher disease model in medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein." Kyoto University, 2015. http://hdl.handle.net/2433/200441.
Повний текст джерелаBRUNIALTI, ELECTRA ATHENA SALOME'. "BETA-GLUCOCEREBROSIDASE MEDIATES MICROGLIAL NEUROPROTECTIVE FUNCTIONS: A POSSIBLE LINK BETWEEN PARKINSON'S AND GAUCHER'S DISEASES." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/811480.
Повний текст джерелаThe Parkinson's disease (PD) evolves over an extended period of time with the onset occurring long before clinical signs begin to manifest. Characterization of the molecular events underlying the PD onset is instrumental for the development of diagnostic markers and preventive treatments but progress in this field is hindered by technical limitations. Risk factors are the obvious target of prevention; mutations in the GBA1 gene, encoding for the lysosomal -glucocerebrosidase (GCase) enzyme, have been associated with the highest risk of PD, while homozygous individuals invariably develop Gaucher’s disease (GD), a pathology characterized by several deficits including neuronal damages. GBA1 mutations impair GCase activity and generate a lysosomal disorder in macrophages considered the hallmark of GD, while in the brain most of the effects of GBA1 mutations have been so far attributed to the GCase deficit in neuronal cells. During my Ph.D. project, I have generated innovative reporter tools and applied different optical imaging approaches to study the activation of brain-protective response in models representative of prodromal phases of PD in vitro and in vivo. The study was focused on nuclear factor erythroid 2-related factor (NRF2), regulating antioxidant/detoxifying response, and the transcription factor EB (TFEB), the master regulator of autophagy and lysosomal pathways, as key signals underlying the early stage of neurodegeneration. In dopaminergic SK-N-BE neuroblastoma cells and in the substantia nigra pars compacta area of the mouse brain, we detected that Nrf2 activation precedes dopaminergic neurodegeneration driven by neurotoxin as demonstrated by cellular, in vivo and ex vivo optical imaging, a finding confirmed by co-localization experiments carried out by immunohistochemistry. Since activation of this transcription factor anticipates dopaminergic neurodegeneration, I focused the study on the cross-talk between a potential PD triggering signal, namely inhibition of the GCase enzyme, and the Nrf2 signaling pathway. Remarkably, I discovered a novel mechanism of microglia-to-neuron communication mediated by cell-to-cell contact, supported by functional actin structures and by an efficient energetic metabolism. Surprisingly, the experiments performed in microglia/neuron co-cultures and in the brain of living mice provided compelling evidence that inhibition of microglial GCase interferes with the ability of these cells to stimulate the NRF2-mediated response in neurons resulting in increased neuronal susceptibility to a xenobiotic. Assays performed in co-culture suggest that counteracting such dysfunction by metabolic compensation could represent a potential therapeutic approach to decrease the risk of neurodegeneration. In conclusion, my thesis demonstrated that the developed reporter systems can be used to study the dynamic modulation of molecular pathways in the living brain; this technology has been developed in particular for the dynamic measurement of oxidative stress and lysosomal/autophagy pathways. Application of these systems allowed to demonstrate that GCase inhibition impairs microglia/neuron communication, thus increasing the susceptibility of neurons to detrimental insults. Taken together, the data identified a novel mechanism underlying the increased risk of neurodegeneration observed in carriers of GBA1 mutations and suggest novel therapeutic strategies for prevention.
Schonauer, Sophie [Verfasser]. "Investigating the GBA1-dependent regulation of GBA2 activity in Gaucher disease / Sophie Schonauer." Bonn : Universitäts- und Landesbibliothek Bonn, 2017. http://d-nb.info/1165650649/34.
Повний текст джерелаMesselodi, Daria <1992>. "Study of pathway alterations in Gaucher disease by induced pluripotent stem cell models." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2021. http://amsdottorato.unibo.it/9592/1/PhD_Thesis_DariaMesselodi.pdf.
Повний текст джерелаFu, Tingting. "Use of Exploratory Data-Mining Techniques to Analyze Associations between Bone-Mineral Density and Relevant Clinical Parameters of Gaucher Disease." Wright State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=wright1344791797.
Повний текст джерелаAyto, Robert Michael. "Investigation of the linkage between Gaucher disease and B-cell disorders including multiple myeloma." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1324513/.
Повний текст джерелаLacerda, Lúcia Maria Wanzeller Guedes de. "Biochemical and molecular genetic studies on gaucher disease in Portugal : the N370S glucocerebrosidae gene mutation." Doctoral thesis, Porto : Edição do Autor, 1998. http://hdl.handle.net/10216/64556.
Повний текст джерелаLacerda, Lúcia Maria Wanzeller Guedes de. "Biochemical and molecular genetic studies on gaucher disease in Portugal : the N370S glucocerebrosidae gene mutation." Tese, Porto : Edição do Autor, 1998. http://catalogo.up.pt/F?func=find-b&local_base=UPB01&find_code=SYS&request=000086735.
Повний текст джерелаAstudillo, Leonardo. "Rôle des sphingolipides dans la cancérogenèse : l'exemple de la maladie de Gaucher." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30401.
Повний текст джерелаSphingolipids represent a major class of lipids, and are important constituents of alleukaryotic cells. They comprise bioactive effectors implicated in key cellular functions,including cell differentiation, proliferation, motility, apoptosis or senescence. Moreover, theirrole in cancer is now well established for numerous sphingolipids. Gaucher disease (GD) is an inherited lipidosis, with autosomal recessive transmission, due tothe deficient activity of glucocerebrosidase (acid beta-glucosidase, encoded by the GBA1gene). This enzyme is one of multiple enzymes of the metabolic pathway of sphingolipids. Itallows the degradation of glucosylceramide (GlcCer) to ceramide. GD is characterised byGlcCer storage of the reticulo-endothelial cells of the liver, spleen and bone marrow (Gauchercells). Evidence has recently been provided for an overrepresentation of various cancers, inparticular multiple myeloma, in GD. However, the underlying mechanisms remainspeculative.The goal of the present thesis work was to approach the bases for the occurrence of cancers inGD. We developed a model of cancerogenesis in GD, using murine models to study thepossible role of microenvironment in cancer development in this disease and to investigate thepossible cellular mechanisms implicated. Our results showed that, in two different murine models (D409V et D409/null) of GD thetumor growth of melanoma cells is increased as compared to controls, both in males andfemales. We have also studied what cell types could be implicated. NKT lymphocytes are notdecreased in the liver and spleen. In addition, the proportion of T CD8+ cells and NK cells isnot reduced in GD mice as compared to controls. In conclusion, we describe the first murine model of melanoma development in Gaucherdisease. The underlying mechanisms for the facilitated growth of melanoma in this mousemodel remain to be further investigated
Yu, Hannah J. "Role of biomarkers in monitoring Gaucher disease and potential of biomarkers to illuminate pathophysiologic pathways." [New Haven, Conn. : s.n.], 2008. http://ymtdl.med.yale.edu/theses/available/etd-12092008-172633/.
Повний текст джерелаOliveira, Fabiane Lopes. "Avaliação da qualidade de vida de pacientes com doença de gaucher, doença de fabry e mucopolissacaridoses." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2010. http://hdl.handle.net/10183/26931.
Повний текст джерелаIntroduction: Gaucher (GD) and Fabry (FD) disease and mucopolysaccharidosis are the most frequent types of lysosomal storage diseases (LSD) treatable with enzyme replacement therapy (ERT). In Brazil, no data are currently available about the quality of life (QoL) of patients with LSD. Objective: To evaluate QoL in a sample of Brazilian patients with GD, FD and MPS using the SF-36 survey. Method: Observational cross-sectional study. The SF-36 survey was administered to cognitively able patients 12 years or older, who were seen in the Medical Genetics Service of Hospital de Clínicas de Porto Alegre, (SGM/HCPA), Porto Alegre, Brazil. Results: Forty-four patients were included (GD = 21; FD = 14; MPS = 9); mean age was 27.5 ± 13.7 years; and 34 (77.2%) were receiving ERT. The analysis of patients receiving ERT revealed a statistically significant difference in the physical function (p = 0.036) and general health (p = 0.030) domains; results suggests that QoL is better in GD. The comparison of patients with GD on ERT (n= 15) and naïve to ERT (n = 6) revealed differences only in the bodily pain domain (p = 0.036). In the analysis of patients with FD, no significant differences were found in SF-36 scores between male patients receiving agalsidase alpha (n = 7) or agalsidase beta (n = 3); heterozygous women had higher scores than hemizygous individuals. In the group of patients with MPS receiving ERT (MPS I = 3; MPS II = 2; MPS VI = 2), mean domain scores ranged from 71.4 ± 48.7 (role-physical) to 44.1 ± 23.4 (bodily pain), whereas in the group of patients not receiving ERT (MPS IV A = 2), scores ranged from 37.5 ± 24.7 (vitality) to 93.7 ± 8.8 (social functioning). Discussion and Conclusion: Although limited because of the small number of patients included, findings suggest that patients with GD receiving ERT have a better QoL than patients with FD or MPS, and that ERT with imiglucerase has a beneficial effect on pain for patients with GD. In the group of patients with FD, scores were higher in heterozygous women, which may be explained by the fact that FD is an X-linked disorder. There seem to be type-specific QoL differences in the group of patients with MPS. Further studies should be conducted to confirm our findings.
Zancan, Ilaria. "Understanding bone alterations in Gaucher disease using the zebrafish animal model: development of a novel pathogenetic paradigm for lysosomal storage disorders." Doctoral thesis, Università degli studi di Padova, 2015. http://hdl.handle.net/11577/3424231.
Повний текст джерелаLe patologie da accumulo lisosomiale sono malattie metaboliche rare a carattere ereditario determinate da carenze di specifici enzimi o trasportatori lisosomiali, che hanno complessivamente un’incidenza di ~1/7000 nuovi nati nella popolazione mondiale. Al giorno d’oggi, almeno 50 disordini genetici sono causati da difetti in enzimi lisosomiali, che determinano l’incompleta degradazione e/o il riciclaggio di molecole a livello intracellulare con conseguente accumulo all’interno del lisosoma dei substrati enzimatici. Nonostante la presenza di proteine lisosomiali in quasi tutti i tessuti ed organi del corpo, l’accumulo del materiale non digerito è generalmente limitato solo a quelle cellule, tessuti od organi nel quale il ricambio del substrato enzimatico è molto elevato. Questa caratteristica determina differenti fenotipi per le varie patologie da accumulo lisosomiale, in quanto diversi organi o cellule possono essere coinvolti. Tra queste patologie, la malattia di Gaucher è la più frequente con un’incidenza di 1 su 200.000 nati vivi nella popolazione mondiale. La frequenza di questa patologia, aumenta drasticamente a 1 su 850 all’interno della popolazione degli ebrei Ashkenazi (Europa dell’Est). Questa malattia è causata da mutazioni a carico del gene che codifica l’enzima lisosomiale β-glucocerebrosidase (GBA). Tali mutazioni determinano l’incorretto ripiegamento della proteina enzimatica che, di conseguenza, non è in grado di degradare il suo substrato, la glucosilceramide, che si accumula nel lisosoma. Una delle caratteristiche di questa patologia è la presenza delle così dette “cellule di Gaucher”, ovvero macrofagi ad elevato contenuto di substrato non degradato, in differenti tessuti. Insieme alla presenza di questi macrofagi alterati, pazienti affetti dalla malattia di Gaucher presentano ingrossamento di fegato e milza (epatosplenomegalia), anemia, trombocitopenia e gravi disfunzioni a carico del sistema scheletrico quali osteonecrosi, riduzione della densità ossea, dolori cronici e frequenti fratture a carico delle ossa lunghe. Si possono distinguere tre sottocategorie di pazienti affetti da GD, generalmente classificati sulla base della presenza e gravità dei difetti a carico del sistema nervoso centrale (SNC). I pazienti affetti da GD di tipo I sono i più frequenti, hanno un’insorgenza della patologia in età tardiva ma non presentano coinvolgimento del SNC. I pazienti affetti da GD di tipo II, invece, manifestano i primi sintomi della malattia fin nei primi anni di vita e spesso i gravi difetti a carico del sistema nervoso possono portare alla morte del paziente. La terza categoria di pazienti, GD tipo III, manifestano i sintomi durante l’età infantile e i difetti neurologici sono meno gravi rispetto a quelli dei pazienti di tipo II. Al giorno d’oggi, questa classificazione basata sulla presenza di difetti neurologici è poco credibile a causa della presenza di fenotipi diversificati all’interno della stessa sottocategoria di pazienti. Il concetto di uno spettro continuo di fenotipi che variano dal meno grave (GD tipo I) al più severo (GD tipo II e III) è più appropriato per descrivere questa patologia. La terapia maggiormente utilizzata per il trattamento della sintomatologia di questa malattia è la terapia enzimatica sostitutiva (ERT), che consiste nella somministrazione di un enzima ricombinante in grado si sopperire alla mancanza della β-glucocerebrosidasi. Nonostante sia ben tollerata dalla maggioranza dei pazienti e sia in grado di far regredire l’ingrossamento di fegato e milza, l’anemia e la trombocitopenia, tale terapia ha effetti davvero limitati sui difetti scheletrici e neurologici. Nel corso degli anni, diversi modelli murini sono stati sviluppati per cercare di comprendere quali siano i meccanismi patogenetici della malattia che inducono questo ampio spettro di fenotipi. Sfortunatamente, la maggior parte di questi modelli animali non sono vitali o non manifestano tutti i difetti della malattia. Lo scopo del mio progetto di dottorato è stato quello di generare un nuovo modello animale per comprendere i meccanismi patogenetici a monte dei difetti ossei della malattia di Gaucher. A tal fine, mi sono avvalsa dell’uso dello zebrafish per la sua facilità di manipolazione e la trasparenza delle uova che permettono di seguire lo sviluppo embrionale fin dalle prime fasi. Utilizzando la tecnica del morfolino e avvalendomi di un modello genetico mutante stabile in zebrafish, ho potuto studiare quale fosse l’effetto della mancanza dell’enzima Gba1 fin dalle prime fasi dello sviluppo embrionale. Questi modelli, inoltre, manifestano insieme ai principali difetti di questa patologia, come l’ingrossamento di milza e fegato e l’anemia, anche i difetti a carico del sistema scheletrico, rendendoli dei buoni modelli per studiare i meccanismi molecolari a monte del fenotipo osseo. Analizzando i principali marcatori molecolari coinvolti nello sviluppo osseo, come col10a1, runx2b e osx, ho potuto evidenziare che i difetti ossei osservati in questi modelli sono determinati da un difetto nel processo di differenziamento degli osteoblasti. Inoltre, l’utilizzo di linee transgeniche di zebrafish nelle quali proteine fluorescenti, come la GFP, sono espresse sotto il controllo di promotori specifici per le principali vie di segnale molecolari, mi ha permesso di individuare alterazioni a carico delle vie di segnale Wnt e BMP in conseguenza alla carenza dell’enzima β-glucocerebrosidasi. Con questo lavoro di dottorato, la caratterizzazione di un nuovo modello animale per lo studio della malattia di Gaucher ha permesso di evidenziare che, disfunzioni a carico di un enzima lisosomiale come la β-glucocerebrosidasi, può determinare alterazioni in segnali molecolari molto importanti per lo sviluppo embrionale, quali il Wnt ed il BMP. Entrambe queste vie molecolari svolgono ruoli importanti nel processo di formazione e mantenimento degli osteoblasti e alterazioni precoci di questi segnali durante l’embriogenesi possono determinare difetti nel processo di differenziamento cellulare da progenitori mesenchimali staminali. I risultati ottenuti durante questo lavoro di dottorato, hanno evidenziato per la prima volta il precoce coinvolgimento di due vie di segnale molecolari, il Wnt e il BMP, nella patogenesi ossea della malattia di Gaucher.
Doneda, Divair. "Doença de gaucher : avaliação nutricional e do gasto energético basal em pacientes do sul do brasil." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2010. http://hdl.handle.net/10183/25128.
Повний текст джерелаINTRODUCTION: Gaucher disease (GD) is an inborn error of metabolism of the group of lysosomal diseases, caused by the deficient activity of the glucocerebrosidase enzyme. The most common types of GD are: type I, which is the most frequent and does not present neurological compromise; type II, which is acute and neuropathic; and type III, which is subacute and neuropathic. All types are characterized by clinical heterogeneity and symptomatic manifestations of various intensity, such as hepatoesplenomegaly and bone and hematological alterations. Some studies have described metabolic alterations, such as increased basal metabolic rate (BMR), that is, hypermetabolism, in untreated patients. The therapy of choice for GD is enzyme replacement therapy (ERT), which can stop many manifestations of the disease. OBJECTIVES: 1) To evaluate BMR by means of indirect calorimetry in patients with GD seen at the Reference Center for Gaucher Disease of Rio Grande do Sul (RCGD); 2) To evaluate the nutritional status of patients included in the study; 3) To relate BMR with clinical conditions presented by patients. METHODS: The present was a prospective, controlled, cross-over study. Patients seen at the RCGD were invited to participate in the study (n=29); of these, 17 agreed to participate (mean age=30.0 ± 17.2 years, male= 8; GD type III=3 patients). Patients with GD type I (n=14; male= 6) were paired by gender, age, and body mass index (BMI) to healthy controls to evaluate BMR. To determine the values of VO2 and VCO2 an ergospirometer was used (MedGraphics Cardiorespiratory Diagnostic Systems, model CPX-D). Patients and controls received previous orientation as to fasting and resting and, on the day of the calorimetry, were weighed and measured in order for the BMI to be calculated. Patients did not present any other morbidity, neither were they making use of any medication that could interfere with BMR. In the statistical analyses, BMR in kcal/kg/day was used. RESULTS: The evaluation of the nutritional status showed that, in the group of patients with GD type I, five patients were overweight; the other were eutrophic; in the group of patients with GD type III, two patients were malnourished; one was eutrophic. Nineteen evaluations of BMR were conducted in 17 patients; two patients conducted the evaluation in the period pre-ERT and after 6 months of ERT. Mean age and mean BMI of patients with GD type I and controls were 32.8 ± 17.6 and 32.1 ± 16.6 years and 23.3 ± 3.1 and 22.4 ± 3.1kg/m2, respectively. The age of patients with GD type III was, respectively, 12, 17 and 20 years. Fourteen patients were receiving ERT (mean time of ERT=6.6 ± 5.3 years; mean enzyme dose=27.1 ± 11.7 UI/kg/inf of imiglucerase). The mean BMR of patients with GD type I on TRE (n=12) was 27.1% higher when compared to controls (p=0.007). When compared to patients not on ERT (n=4), the BMR of patients on ERT (n=12) did not show any difference (p=0.92). Comparing the BMR of patients on ERT and that of their controls with the BMR estimated by the Harris-Benedict equation, we observed that patients showed a 6.3% higher BMR than the estimated (p=0.1), while the BMR of their controls was 17.0% lower than the estimated (p=0.001). The BMR of patients with GD type III was, respectively, 14%, 72% and 16% higher than the estimated by the Harris-Benedict equation. No significant association was found between BMR and the following variables: age; weight; height; severity score; amount of enzyme received; age at beginning of ERT; time of treatment; and presence or absence of megalies. The correlation between BMR and BMI was negative and significant, as expected. DISCUSSION/CONCLUSIONS: The nutritional status classified by BMI showed that most patients with GD type I were eutrophic; however, one third of the patients showed pre-obesity. Two of the three patients with GD type III were malnourished. All patients, even on ERT, showed a significantly higher BMR when compared to controls. In conclusion, ERT was not able to normalize the hypermetabolism of these patients.
Doneda, Divair. "Avaliação do estado nutricional e de parâmetros da homeostase de energia em pacientes com Doença de Gaucher." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/71632.
Повний текст джерелаINTRODUCTION: Gaucher disease (GD) is an inborn error of metabolism, caused by the deficient activity of the glucocerebrosidase enzyme and is divided into three types: type I, which is the most frequent and does not present neurological compromise; type II, which is acute and neuronopathic; and type III, which is subacute and neuronopathic. All types are characterized by clinical heterogeneity and symptomatic manifestations of varied intensity, such as hepatosplenomegaly, hematologic dysfunction, bone pain; energy homeostasis dysfunction is also present. The choice therapy for GD is enzyme replacement therapy (ERT). OBJECTIVE.To assess the nutritional status and the energy homeostasis in patients affected by Gaucher Disease under enzyme replacement therapy. METHODS.This present study is composed of 4 stages. Stage 1) Systematic literature review on GD type I nutritional aspects. Stage 2) Assessment of data revolving around nutritional status of the patients cohort followed at the GD Reference Center in Rio Grande do Sul(CRDG/RS; n= 38; GD type I=35; GD type III= 3. Stage 3) Assessment of basal energetic expenditure by indirect calorimetry in GD type III patients at CRDG/RS. Stage 4) Assessment, by means of controlled transversal study, of ghrelin, leptin and adiponectin levels in GD- I patients, age over 18 yo and under ERT for at least 6 months (n=15); the patients were pair matched with healthy controls for sex, age and BMI. RESULTS: Stage 1) 175 studies were found, of which 28 met the inclusion criteria. These studies have shown ERT is associated to: growth normalization in children and teenagers with delayed development; partial correction of hypermetabolism and glycemic profile dysfunctions; and increase in weight as well as insulin resistance and development of Diabetes mellitus type 2 in adults. Stage 2) The anthropometric data of adult patients with GD type I (n=31) pointed out fourteen showed overweight or obesity level 1, and all patients aged under 18yo showed adequate weight and height. The patient’s age showed high correlation with BMI and ferritin levels. BMI presented correlation with ferritin and the latter with total cholesterol and LDL- cholesterol. Total cholesterol showed correlation with HDL, with LDL and negative correlation with chitotriosidase. The subgroup comprising those who were over 18 years of age (n=16) at the beginning of treatment had a significant increase in BMI after ERT (p=0,001) and those beginning treatment under the age of 16 showed (n=10) significant increase in the z-score for height and BMI (p=0,004 and p= 0,032, respectively). Stage 3) GD type III patients showed hypermetabolism and two of them (2/3) were malnourished. Stage 4) The median of ghrelin, leptin and adiponectin levels of patients did not differ from that of the controls. The ghrelin and adiponectin levels presented positive correlation between themselves, with HDL-cholesterol, and inverse correlation with BMI, waist circumference, and triglycerides. The leptin levels presented inverse correlation with LDL-cholesterol and direct correlation with BMI, waist circumference, enzyme dose, triglycerides, insulin, and HOMA-IR. Eight patients (n=15) met the criteria for metabolic syndrome, four of which had insulin resistance, as measured by the HOMA-IR index. DISCUSSION AND CONCLUSIONS: Data from the systematic review showed the treatment with imiglucerase improves growth in children and adolescents with GD type I, this meets the findings in this cohort. In relation to the patients assessed, the nutritional status measured by BMI showed that almost half of the GD type I patients were overweight and that ERT seems to contribute to this finding. Hypermetabolism in GD type III patients seems to be a biomarker of the severity of this disease. Leptin presented high association with insulin and with the HOMA-IR index, and may eventually become a biomarker to evaluate early evidence of insulin resistance in GD patients. Weight increase, metabolic syndrome and insulin resistance seem to be frequent in GD type I patients. Further research is necessary to investigate the findings herein researched.
Kostandini, Gentian. "Potential Impacts of Pharmaceutical Uses of Transgenic Tobacco: The Case of Human Serum Albumin and Gaucher's Disease Treatment." Thesis, Virginia Tech, 2004. http://hdl.handle.net/10919/10119.
Повний текст джерелаMaster of Science
Camelier, Marli Teresinha Viapiana. "Avaliação do uso de amostras de leucócitos impregnados em papel filtro para o diagnóstico de doenças lisossômicas." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/150661.
Повний текст джерелаBackground: Lysosomal Disorders (LDs) are genetic conditions, mostly inherited in autosomal recessive fashion, usually characterized by a deficiency of specific lysosomal enzymes involved in the synthesis, degradation, storage or transportation of macromolecules necessary for normal functioning of the organism. Typically, the non-degraded substrate is progressively accumulated in lysosomes, with structural and functional repercussions, leading to characteristic signs and symptoms. Affected patients present a wide range of clinical manifestations, which may include organ dysfunction, skeletal anomalies, neuronal involvement, etc. The diagnosis is normally made through identification of the specific enzyme deficiency in white blood cells from a sample of peripheral blood, usually performed in reference laboratories. The transporting of a liquid sample can be a problem when the test orderer is located far from the reference center or in a foreign country, as often the blood sample arrives at the laboratory in poor condition and cannot be properly analyzed. Aim: The main aim of this study was to make available a new technique that is simpler, safer and more accessible, using leukocytes impregnated on filter paper (LIFP) as a new tool for the biochemical diagnosis of patients with LSDs. Methods: This study involved samples of patients with previously confirmed diagnosis of selected LSDs (a convenience sample, as these are rare diseases, with individual incidences around 1:100.000 live newborns). Patients with an established diagnosis of MPS IVA, Krabbe Disease, Gaucher’s disease and Pompe disease regardless of sex and/or age, cared for at the Genetics Service of HCPA and who agreed to participate were included in the study. The negative reference group comprised blood samples from 50 healthy adults of both genders. Results: The results obtained in the enzymatic assays of patients with MPS IVA, Krabbe Disease, Gaucher’s disease, and Pompe disease indicated that the analyzed enzymes in LIFP samples allowed the identification of all patients, with sensitivity of 100%. The stability tests performed in LIFP samples indicated that samples, when maintained at 4ºC, were stable for at least 30 days. Conclusions: In the conditions used, LIFP samples were shown to be adequate for a reliable identification of patients with MPS IVA, Krabbe Disease, Gaucher’s disease, and Pompe disease. Blood samples on filter paper are more stable and reliable for transportation, indicating that this may be an important tool to facilitate the identification of patients with LSDs, particularly those living in areas with difficulties for the shipment of liquid samples to reference cervices.
Reed, M. "Characterisation of pathogenic pathways within the bone microenvironment of Gaucher disease which contribute to bone pathology and haematological malignancy." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1553387/.
Повний текст джерелаBurke, Derek Gerard. "Interplay between Glucocerebrosidase 1 and Glucocerebrosidase 2 : potential implications for the pathogenesis of Gaucher and Parkinson's diseases." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1571208/.
Повний текст джерелаMagalhães, Tatiana de Sá Pacheco Carneiro de. "O tratamento da doença de Gaucher no Sistema Único de Saúde: o caso do Rio de Janeiro." Instituto Fernandes Figueira, 2013. https://www.arca.fiocruz.br/handle/icict/8266.
Повний текст джерелаFundação 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.
Chaves, Rigoberto Gadelha. "Rastreamento populacional para Doen?a de Gaucher em Tabuleiro do Norte-CE." Universidade Federal do Rio Grande do Norte, 2011. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13345.
Повний текст джерелаBackground. Gaucher Disease (GD) is a hereditary lysosomal storage disorder characterized by the accumulation of glucosylceramide, mainly in the cells of the reticuloendothelial system, due to a deficiency of the enzyme acid β-glucosidase (GBA). Diagnosis is usually based on measurement of GBA activity in peripheral leukocytes. The purpose of this study was to evaluate the ability of screening for GBA and chitotriosidase activity using Dried Blood Spots on Filter Paper (DBS-FP) to identify individuals at high risk for GD in high-risk populations such as that of Tabuleiro do Norte, a small town in Northeastern Brazil. Methods. Between June 1, 2007 and May 31, 2008, 740 consented residents and descendants of traditional families from Tabuleiro do Norte were submitted to screening with DBS-FP. Subjects with GBA activity <2.19 nmol/h/mL were referred to analysis of GBA and chitotriosidase activity in peripheral leukocytes and in plasma, respectively. Subjects at highest risk for GD (GBA activity in peripheral leukocytes <5.6 nmol/h/mg protein) were submitted to molecular analysis to confirm diagnosis. Results. Screening with DBS-FP identified 135 subjects (18.2%) with GBA activity <2.19 nmol/h/mL, 131 of whom remained in the study. In 10 of these (7.6%), GBA activity in leukocytes was 2.6 5.5 nmol/h/mg protein. Subsequent molecular analysis confirmed 6 cases of heterozygosity and 4 normals for GD. Conclusion. DBS-FP assay was shown to be an effective initial GD screening strategy for high-prevalence populations in developing regions. Diagnosis could not be established from GBA activity in leukocytes alone, but required confirmation with molecular analysis
A doen?a de Gaucher (DG) ? uma patologia de dep?sito de gordura nos lisossomos, de heran?a autoss?mica recessiva, caracterizada pelo ac?mulo do substrato glicosilceramida, principalmente nas c?lulas do sistema reticuloendotelial, em raz?o da defici?ncia da enzima β-glicosidase ?cida (GBA). O diagn?stico, comumente, ? feito pela dosagem da atividade da GBA em leuc?citos perif?ricos. Tabuleiro do Norte (TN), Cear?, Brasil, ? um munic?pio com cerca de 28.000 habitantes com a preval?ncia da DG de 1:4.000 habitantes, possivelmente a mais elevada do Brasil. O objetivo da disserta??o ? avaliar o rastreamento para DG realizado em TN com base na an?lise das atividades enzim?ticas da GBA e da quitotriosidase em amostras Sangue Seco em Papel de Filtro (SSPF). Entre 01 de junho de 2007 a 31 de maio de 2008, 740 indiv?duos residentes e descendentes de fam?lias de TN participaram do rastreamento para DG a partir de amostras de SSPF. Indiv?duos com atividade GBA<2,19 nmol/h/mL foram selecionados para an?lise da atividade da GBA e da quitotriosidase em leuc?citos perif?ricos e no plasma, respectivamente. Os indiv?duos com maiores riscos de DG (atividade de GBA em leuc?citos perif?ricos <5,6 nmol/h/mg de prote?na) foram referenciados para an?lise molecular para confirma??o diagn?stica. A triagem com amostras de SSPF identificou 135 indiv?duos (18,2%) com atividade da GBA<2,19 nmol/h/mL, dos quais 131 permaneceram no estudo. Em dez destes (7,6%), a atividade da GBA em leuc?citos variou de 2,6-5,5 nmol/ h/mg de prote?na, considerados suspeitos da DG. A an?lise molecular subsequente revelou, entretanto, que se tratava de seis indiv?duos heterozigotos para a muta??o G377S e, em quatro deles, n?o foram identificadas muta??es da DG. A an?lise enzim?tica de amostras de SSPF mostrou ser uma estrat?gia eficaz de triagem da DG em popula??es com alto risco, mas a medida da atividade da GBA em leuc?citos deve ser realizada para confirma??o diagn?stica. O diagn?stico de DG em indiv?duos assintom?ticos n?o deve ser firmado baseando-se apenas na an?lise da atividade da GBA em leuc?citos, sendo necess?ria, tamb?m, a confirma??o diagn?stica pela an?lise molecular
Decroocq, Camille. "Conception et synthèse de nouvelles classes d'iminosucres d'intérêt thérapeutique : chimie click, multivalence et maladies génétiques rares." Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAF043/document.
Повний текст джерелаRecently an innovative concept for the treatment of lysosomal diseases as emerged called pharmacological chaperone. Pharmacological chaperones are reversible inhibitors of the deficient glycosidases involved in these diseases. These molecules are able, at sub-inhibitory concentrations, to stabilize the enzymes and rescue them from the destruction by the quality control system of the endoplasmic reticulum. A part of the catalytic activity of the enzyme could be restored. Iminosugars are known to be an important class of pharmaceutical chaperones. During this PhD work, novel classes of mono- and multivalent iminosugars were designed and synthesized in order to identify novel pharmacological chaperones for the glycosidase: β-glucocerebrosidase involved in Gaucher’s disease and novel inhibitors of the α-glucosidases involved in the destruction of the defective protein delF508CFTR in cystic fibrosis. Several strategies were applied to achieve this aim. These strategies consist in the use of a synthetic methodology of palladium catalyzed alkenes diamination, the use of an efficient methodology to synthesize a library of novel iminosugars by click chemistry and the use of multivalency. A full study on the impact of multivalency on glycosidases inhibition was also completed by changing crucial structural parameters including valency, scaffold, linker and ligand. The first strong multivalent effect on glycosidases inhibition up to four orders of magnitude was reported with multivalent iminosugars based on β-cyclodextrin or C60 fullerene cores
Goldim, Mariana Pereira de Souza. "Validação das técnicas fluorimétricas para estabelecimento da atividade específica da beta-glicosidase e quitotriosidase de sangue impregnado em papel filtro para o diagnóstico da doença de Gaucher." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/49005.
Повний текст джерелаGaucher disease (GD) is the most frequent Lysosomal Storage Disorder with a prevalence of 1:50,000. It is caused by the deficiency of acid betaglucosidase (GBA), generating glucosylceramide (glucocerebroside) accumulation in the lysosomes. Another enzyme related to GD is chitotriosidase (CT), which activity is increased in patients up to 1000 times. Currently the diagnosis is based on the specific activity of enzymes in leukocytes or fibroblasts. The use of dried blood spots (DBS) has been extended, but only as screening, because there is no validated specific activity of the enzymes. The use of DBS has several advantages, such as easy transport and easy storage of samples, smaller reaction volume and safety of handling samples. This study aims to validate fluorometric techniques for establishing specific activity of the GBA and CT in DBS eluted with universal buffer (20 mmol/L sodium phosphate, pH7.0) by correcting for sample volume quantification of total protein. Moreover, standard screening techniques in DBS and standard diagnosis techniques in leukocytes for GD have been miniaturized. New reference values and cut-off points were established for all techniques. It was possible to differentiate healthy controls from patients with GD using miniaturized techniques in DBS and leukocytes. The specific activity of DBS proved valid and coefficients of variation were acceptable. The enzymatic stability was analyzed by 21 days of storage at 4° C and it was observed that there is a decrease of the activity of GBA, but not of CT. Thus the specific activity on DBS can be used as a reliable screening method and as diagnosis of GD.
Henning, Karen [Verfasser]. "Adeno-associated viral gene transfer to prevent the cellular phenotype of cortical organotypic brain-slice cultures derived from Gaucher’s disease type II mice. / Karen Henning." Berlin : Freie Universität Berlin, 2014. http://d-nb.info/1050978242/34.
Повний текст джерелаZunke, Friederike [Verfasser]. "Characterisation of the Lysosomal Integral Membrane Protein Type-2 (LIMP-2) and its interaction with b-Glucocerebrosidase: implications for Parkinson and Gaucher Disease / Friederike Zunke." Kiel : Universitätsbibliothek Kiel, 2018. http://d-nb.info/1172288046/34.
Повний текст джерелаLUGARI, SIMONETTA. "Caratterizzazione del profilo metabolico, dell’entità del danno epatico e dello stile di vita in una coorte di pazienti adulti con malattia di Gaucher." Doctoral thesis, Università degli studi di Modena e Reggio Emilia, 2022. http://hdl.handle.net/11380/1278346.
Повний текст джерелаBackground Gaucher disease (GD) is a rare inherited lysosomal storage disorder, characterized by glycosphingolipids accumulation in cells of the reticulo-endothelial system due to deficiency of the lysosomal enzyme acid beta-glucosidase. Hepato-splenomegaly, cytopenia and bone disease represent the main features of type 1 GD. GD patients present a peculiar metabolic profile characterized by increased energy expenditure, systemic inflammation, peripheral insulin resistance and hypolipidemia. Liver disease is frequent and variable, ranging from benign hepatomegaly to fibrosis or cirrhosis. Enzyme replacement therapy and substrate reduction therapy have proven to be very effective on visceral and bone disease and to improve patients’ morbidity and quality of life. Aging GD patients, as the general population, may develop lifestyle-related metabolic risk factors with a potential impact on morbidity and mortality. Description of the studies Limited data are available about body composition, metabolic features, liver disease and lifestyle in GD. This project was designed to characterize the metabolic profile and the liver disease burden in a cohort of adult type 1 GD patients and to evaluate their relationship with GD variables and lifestyle. Patients were evaluated at baseline and follow-up visits, collecting data about GD severity and therapy, anthropometric and metabolic parameters; lifestyle habits were evaluated by validated questionnaires; body composition was assessed by DEXA and liver disease by abdominal ultrasound, magnetic resonance and liver transient elastometry (Fibroscan®). Preliminary study - In a cohort of 37 adult type 1 GD patients, a notable proportion (19%) showed significant liver fibrosis, defined as liver stiffness > 7 kPa, which was associated with GD severity features and a short therapy duration. Among patients on stable ERT, liver fibrosis was also significantly associated with the metabolic syndrome components, suggesting a potential role of metabolic comorbidities in liver disease progression. Study 1 – Within a subgroup of 20 patients of the cohort, metabolic comorbidities were widely represented and liver steatosis, defined as CAP value ≥ 250 dB/min, was detected in 40% of them. Significant steatosis was associated with metabolic syndrome, but not with GD severity variables and therapy duration. Moreover, patients with liver steatosis showed a worse metabolic profile and higher liver stiffness than the counterpart without steatosis. Study 2 – Then, we aimed at evaluating metabolic and liver-related comorbidities in relation to lifestyle and body composition. Analysis of the dietary and physical activity questionnaires showed, respectively, a high prevalence of unbalanced diet and physical inactivity. Body composition evaluation showed an increased fat mass and decreased bone and lean mass. Unbalanced diet and sedentariness were positively associated with indices of adiposity and metabolic syndrome features, suggesting that unhealthy lifestyle had a potential role on metabolic and liver complications in GD patients on stable ERT. Study 3 – Finally, we aimed at evaluating changes in metabolic profile over time and at identifying predictors of liver-related outcome in a longitudinal follow-up study. Conclusions Cardiometabolic risk factors, liver steatosis and fibrosis are highly prevalent and seem to be mainly related to unhealthy lifestyle in our adult GD cohort on stable therapy. For that reason, a cardiometabolic and lifestyle assessment in GD patients is advisable. Moreover, lifestyle changes and control of metabolic risk factors should be part of the therapeutic approach for GD patients, preferably by a multidisciplinary team, aimed at preventing metabolic and liver-related complications
Turcatel, Elias. "Investigação da capacidade antioxidante, perfil inflamatório e dano ao DNA em pacientes com Doença de Gaucher tratados com a terapia de reposição enzimática." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/129765.
Повний текст джерелаGaucher disease (GD) is a lysosomal storage disorder caused by a mutation in the gene encoding β-glucosidase enzyme, this enzyme deficiency leads to glucosylceramides accumulation in the lysosomes of the reticulum endothelial system. GD divided into three types, where in type I is the mildest and most prevalent form of disease. The consequences of this disease include hepatosplenomegaly, bone impairments, hematologic manifestations and neurodegeneration, but pathophysiology mechanisms are still not well elucidated. Therefore, in order to clarify the pathophysiology involved in GD, the present study evaluated reactive oxygen species production, superoxide dismutase, catalase and gluthatione peroxidase activities, nitrite levels, immunocontent of iNOS and pNF-κB, DNA damage and sulfhydryl content in differents components of blood from affected individuals.Patients were divided into two groups: controls with negative diagnosis to GD and patients diagnosed to GD type I treated with enzyme replacement therapy. Blood were collected 5 minutes before the treatment. Results showed that superoxide dismutase activity was reduced in erythrocytes while gluthatione peroxidase activity was increased in plasma of GD patients. Nitrite levels and pNF-κB immunocontent were significantly increased in plasma and leukocytes, respectively. Comet assay was performed in whole blood and indicated DNA damage. We also observed an oxidative damage to proteins elicited by decreased sulfhydryl content in plasma and erythrocytes. Our findings suggest that patients with GD, even in treatment, have altered oxidative/nitrative status and inflammatory parameters, as well as evidence of DNA damage in blood, what could be at least in part, associated with pathophysiology of GD.
Zamoner, Luis Otavio Bunhotto. "Síntese de imunoaçúcares modificados e avaliação da atividade biológica." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/60/60138/tde-21052012-103516/.
Повний текст джерелаGlucosidases are enzymes that catalyze the hydrolysis of glycosidic bonds releasing monosaccharide units from a non-reducing end of an oligosaccharide or glycoconjugate. Iminosugars are polihydroxilate piperidinic alkaloids isolated from plants (Morus alba) and microorganisms (Bacillus), such as nojirimicin (NJ) (1) and 1- deoxynojirimicin (2), which are described as glucosidase inhibitors. The potential use of these inhibitors in the treatment of viral infection, tumoral growing, metastasis, diabetes, Gaucher´s disease and osteoarthritis has stimulated the scientific community on the search for novel iminosugar derivatives. Thereby, the synthesis of pseudodisaccharides, having both iminosugar and glycopyranose residues, represents an interesting strategy to obtain these derivatives, despite the challenges involved in generating the link between these two sugars. For this reason, we have used click chemistry as a tool to introduce a 1,2,3-triazole bridge between the sugars from the coupling of azide-glycosides with N-propargyl-iminosugar. Thus, the synthesis of N-propargyl-iminosugar (73), containing the terminal acetylene function, was performed in five steps, and was used in the 1,3-dipolar cycloaddition reaction with three glycosidic derivatives containing the azide group at anomeric (C-1), C-3 or C-6 positions. By applying this CuAAC (Copper(I)-catalyzed Azide-Alkyne Cycloaddition), three novel pseudo-disaccharides (77, 81 and 85) were synthesized in moderate yields and then, evaluated in -D-glucosidase assays isolated from Sacharomyces cerevisiae. In these preliminary test, compound 77 was the most active from the series, which was able to inhibit 40% of the enzyme activity at 1 mM. These results encourage us to perform new experiments, notably the determination of Ki and evaluation towards HIV replication. Thus, a contribution regarding carbohydrate chemistry and treatment of the supracited diseases was achieved by the synthesis of these pseudodisaccharides.
Stauffert, Fabien. "Conception et synthèse d’iminosucres di- à tétravalents comme sondes mécanistiques et agents thérapeutiques potentiels." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAF061/document.
Повний текст джерелаBecause multivalent iminosugars represent, as potent glycosidase inhibitors, privileged structures for the design of novel drugs, we took a particular interest in this class of compounds for the treatment of two rare genetic diseases. The first research topic was dedicated to the synthesis of di- to tetravalent iminosugars in the 1-deoxymannojirimycin series in order to inhibit the endoplasmic reticulum α1,2-mannosidase I involved in the destruction of delF508-CFTR, the mutant protein responsible of cystic fibrosis. A strong multivalent effect for restoring its activity in cells was reported with a trivalent analogue based on pentaerythritol. This submicromolar corrector was found to be 140-fold more potent than the corresponding monovalent model. The second research topic focused on the identification of novel pharmacological chaperones of the β-glucocerebrosidase, the lysosomal enzyme involved in Gaucher’s disease. For this purpose, we developed a series of heterodivalent iminosugars designed to both bind to the active site and a secondary site of the enzyme. This goal could not be reached yet, nevertheless we identified monovalent chaperones which were able to fourfold increase β-glucocerebrosidase activity in G202R cell lines. Next to these main research topics, a mechanistic probe based on a multivalent C-glycoside was also developed to investigate the multivalent effect of iminosugar clusters in glycosidase inhibition
Hammoudi, Nadjib. "Contribution à l'étude de la désadaptation cardiovasculaire à l'effort : évaluation des pressions de remplissages à un faible niveau de charge et réponse cardio-circulatoire lors d'un exercice dynamique maximal." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066598/document.
Повний текст джерелаDespite normal investigations at rest, latent heart failure can be observed in a number of patients during exercise. We investigated the hypothesis of an impairment of cardiovascular reserve in two pathophysiological models: - in patients at high risk of heart failure with preserved ejection fraction, we measured left ventricular filling pressures at low exercise level in order to unmask early stages of left ventricular diastolic dysfunction;- moreover, using combined echocardiography and cardiopulmonary exercise testing, a comprehensive study of cardiovascular response to maximal exercise was performed in patients with sickle cell anemia which was chosen as a model of chronic high-output states. We showed that very low exercise level could unmask early stage heart failure with preserved ejection fraction. These results, initially observed using Doppler echocardiography, were confirmed by direct invasive measurement of left ventricular filling pressure during exercise. In patients with sickle cell anemia, we found a decrease of cardiac output response to exercise. This alteration of cardiovascular reserve was characterized by a chronotropic incompetence and a blunted left ventricular preload reserve. The pathophysiological data provided by our studies may help improve and optimize management of patients with heart failure. The stress protocols which have been developed and used in our investigations could be useful to study other models of heart diseases
Castilla, López Javier. "Carbohydrate manipulations towards high-mannose oligosaccharides." Doctoral thesis, Universitat Rovira i Virgili, 2012. http://hdl.handle.net/10803/87113.
Повний текст джерелаThe final goal of this thesis is the development of strategic methods fro the synthesis of well-defined 1,2-linked oligosaccharides and S-linked thio-analogues through different polymerization techniques. These structures form a complex group of biomolecules with an unsurpassed structural diversity, performing a variety of biological functions. In this context, the present work aimed to develop new procedures in carbohydrate chemistry, focusing in the oligomerization reactions. Thus, efficient syntheses have been studied for accessing the suitable carbohydrate based monomers (including epoxides, episulfides, carbonates and tiocarbonates). Unexpectedly, the synthesis of epithiocarbohydrates afforded carbohydrate-derived 1,3-oxazolidine-2-thiones. These compounds have proved to be quite attractive as new enzyme inhibitors for Gaucher disease. All enzyme inhibition studies can be found in the manuscript.