Thesis (M.S.)--University of Alabama at Birmingham, 2006. / Title from first page of PDF file (viewed on June 30, 2007). Includes bibliographical references (p. 69-73).

Submitted by SILVANO SALGUEIRO GERALDES (silvanoport@hotmail.com) on 2018-11-14T14:59:48Z No. of bitstreams: 1 TUDO JUNTO FINAL UFA 2.pdf: 2314651 bytes, checksum: 479534b0afd7e5f086434a40d21bcc42 (MD5) / Rejected by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo as orientações abaixo: problema 1: Capa Na capa, acima do autor, deve conter os seguintes dados: UNIVERSIDADE ESTADUAL PAULISTA “Júlio de Mesquita Filho” FACULDADE DE MEDICINA VETERINÁRIA E ZOOTECNIA CAMPUS DE BOTUCATU Problema 2: ficha catalográfica No arquivo submetido não consta a ficha catalográfica, item obrigatório para submissão. A ficha deve ser incluída no arquivo PDF logo após a folha de rosto do seu trabalho. Assim que tiver efetuado as correções submeta o arquivo, em formato PDF, novamente. Agradecemos a compreensão. on 2018-11-19T14:54:20Z (GMT) / Submitted by SILVANO SALGUEIRO GERALDES (silvanoport@hotmail.com) on 2018-11-19T18:43:29Z No. of bitstreams: 1 DISSERTACAO TUDO JUNTO.pdf: 2708732 bytes, checksum: bbcf9a09041f7c917d0139d374b20244 (MD5) / Rejected by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br), reason: fazer as correções conforme informado. on 2018-11-20T18:08:47Z (GMT) / Submitted by SILVANO SALGUEIRO GERALDES (silvanoport@hotmail.com) on 2018-11-20T19:01:47Z No. of bitstreams: 1 qualificacao total 20 11 tarde.pdf: 2708926 bytes, checksum: b9570de413ca4e3c069dbc02803bfc8d (MD5) / Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2018-11-21T10:31:42Z (GMT) No. of bitstreams: 1 geraldes_ss_me_bot.pdf: 2708926 bytes, checksum: b9570de413ca4e3c069dbc02803bfc8d (MD5) / Made available in DSpace on 2018-11-21T10:31:42Z (GMT). No. of bitstreams: 1 geraldes_ss_me_bot.pdf: 2708926 bytes, checksum: b9570de413ca4e3c069dbc02803bfc8d (MD5) Previous issue date: 20-09-20 / A Hemodiálise Intermitente (HDI) é uma modalidade de substituição renal, que vem sendo utilizada nas últimas décadas na veterinária nos casos de remoção de drogas, distúrbios hidroeletrolíticos, lesão renal aguda e doença renal crônica (DRC) em crise urêmica. O objetivo do estudo consistiu em avaliar o efeito da hemodiálise intermitente, instituída em cães DRC, em comparação aos manejados apenas com tratamento clínico, sem diálise, visando proporcionar uma melhor qualidade de vida. Foram selecionados 12 cães com DRC no estádio III e 25 cães DRC no estádio IV pelos critérios de inclusão, randomizados em grupo controle (n=6) no estádio III e (n=11) no estádio IV, onde foi preconizado apenas tratamento clínico e fluidoterapia, e grupo hemodiálise (n=6) no estádio III e (n=14) no estádio IV, em que além do tratamento clínico, foi realizada a hemodiálise intermitente. As coletas de sangue para avaliação laboratorial foram realizadas antes e após a fluidoterapia e antes e após a hemodiálise intermitente. As intercorrências e os parâmetros clínicos foram avaliadas a cada 30 minutos durante a HDI. A eficácia das sessões de HDI foi avaliada por meio da mensuração da taxa de remoção da ureia (URR). A instituição do tratamento dialítico promoveu uma eficaz diminuição das concentrações séricas de ureia, creatinina e fósforo em ambos estádios, porém com diminuição da sobrevida dos cães no estádio III. Apesar da evidente remoção dos compostos nitrogenados, é necessária uma constante avaliação do perfil hematológico e bioquímico sérico para evitar distúrbios derivados da redução indesejada dos compostos, para evitar danos posteriores ao paciente. / Intermittent Hemodialysis (IHD) is a modality of renal replacement that has been used in the last decades in the veterinarian in cases of drug withdrawal, hydroelectrolytic disorders, acute kidney injury and chronic kidney disease (CKD) in uremic crisis. The objective of the study was to evaluate the effect of intermittent hemodialysis, instituted in dogs CKD, in comparison to those managed only with clinical treatment, without dialysis, in order to provide a better quality of life. Twelve dogs with stage III CKD and 25 stage four CKD dogs were selected by inclusion criteria, randomized in a control group (n = 6) in stage III and (n = 11) in stage IV, where only clinical treatment was recommended and and hemodialysis group (n = 6) in stage III and (n = 14) in stage IV, in which, in addition to clinical treatment, intermittent hemodialysis was performed. Blood samples for laboratory evaluation were performed before and after fluid therapy and before and after intermittent hemodialysis. Intercurrences and clinical parameters were assessed every 30 minutes during IHD. The efficacy of the IHD sessions was assessed by measuring the urea removal rate (URR). The establishment of the dialytic treatment promoted an effective decrease in the serum concentrations of urea, creatinine and phosphorus in both stages, but with a decrease in the survival of dogs in stage III. Despite the obvious removal of the nitrogen compounds, a constant evaluation of the hematological and serum biochemical profile is necessary to avoid disorders derived from the undesired reduction of the compounds, to avoid further damage to the patient.

Inledning: Mikroskopisk analys av urinsediment anses i dagsläget vara gold standard inom urinsedimentdiagnostik, trots att metoden ofta är otillräckligt standardiserad. En rad automatiserade instrument, såsom UF-5000, finns idag tillgängliga och kompenserar för problematiken med den gamla metoden. Analys av urinsediment är avgörande vid flertal njursjukdomar, där bland annat erytrocyter, leukocyter, epitelceller, cylindrar och kristaller är av stort diagnostiskt värde. Syfte: Syftet var att utvärdera det automatiserade urinpartikelinstrumentet UF-5000 samt att jämföra metoden med manuell ljusmikroskopering av urinsediment. Metod: Vid metodjämförelse analyserades 69 prover med instrumentet UF-5000 samt i mikroskop. Data bearbetades med Passing Bablok-regression, Bland-Altman differensanalys samt Spearmans rangkorrelationkoefficient. Resultat: Statistisk signifikant skillnad förekom vid metodjämförelsen. Utvärderingen av instrumentet visade hög mätnoggrannhet med undantag för variationskoefficienten vid låg leukocytkoncentration samt avvikelser för instrumentets linjäritet. Diskussion: Då ljusmikroskopering av urinsediment är en otillräckligt standardiserad metod kunde statistiskt signifikanta skillnader ses, vilket kan bero på den bristande referensmetoden. Fortsatta studier där automatiserad metod jämförs med en mer standardiserad manuell mikroskopi är av stor vikt. Även reducering av cut-off för diverse parametrar kan vara aktuellt. Instrumentutvärdering visade en generell mätnoggrannhet med enstaka undantag vilket kan bero på felhantering vid analys. För vidare analys av linjäritet skulle ett ytterligare instrument som komplement kunna användas. / Introduction: Microscopy is gold standard for urine sediment analysis, although the method is often insufficiently standardized. Several automated instruments, such as UF-5000, are commercially available on the market. Urine sediment analysis is crucial for diagnosis of kidney and urinary tract diseases where elements such as erythrocytes, leukocytes, epithelial cells, casts and crystals can be identified. Aim: The aim was to evaluate the performance of UF-5000 and compare the method with manual microscopic analysis of urine sediment. Method: Analysis with UF-5000 and microscopy was conducted on 69 samples. Data were processed with Passing Bablok-regression, Bland-Altman bias plot and Spearman's rank order correlation. Result: Comparison showed statistical significance between the two methods. Performance evaluation showed high accuracy apart from the coefficient of variation for low concentration of leukocytes and systematic error for linearity. Discussion: Since microscopy of urine sediment is an insufficiently standardized method, differences were acknowledged caused by discrepancies in the reference method. Further studies where UF-5000 is compared to a more standardized manual microscopy with a larger amount of pathological urine samples is of great importance. Reduction for cut-off may also be relevant. For further analysis of linearity, an additional instrument should be used as a complement.

Made available in DSpace on 2014-12-17T14:03:43Z (GMT). No. of bitstreams: 1 DanielSCM_DISSERT.pdf: 1478409 bytes, checksum: 4c3dc0be5dfc867e58e628d7a5b789a7 (MD5) Previous issue date: 2013-03-04 / The use of medicinal plants to cure and treat various diseases is a common practice in the world and in Brazil. In several regions of the Brazil?s Northeast, the cactus Cereus jamacaru, known as mandacaru, is used popularly as a treatment to many diseases, including those related to heart respiratory diseases, gastric ulcers, scurvy, and kidney diseases. However, there is a scarcity in the scientific literature that proves scientifically the popular application of this cactus. Like other plants, Cereus jamacaru synthesizes several potentially bioactive molecules, like as polysaccharides. In this work, three polysaccharides-rich aqueous extracts, MCA80, MPM and MCP60, were obtained from this plant and analyzed chemically, as well as their cytotoxic and antioxidant potential. The data showed that all extracts consist mainly of polysaccharides (89.42 to 95.76%), but also protein (> 2%) and phenolic (3 to 8.87%) contaminants were detected. All extracts are rich in galactose, glucose and mannose. In addition, glucuronic acid was found in MCA80 and MCP60. The extracts showed total antioxidant capacity ranged from 55.21 to 68.13 of ascorbic acid equivalents (AAE). Besides, they exhibited reducer power and cupric chelation in a dose-dependent manner. None of the extracts inhibited the MTT reduction in the presence of prostate tumor cells (PC-3). However, MCP60 was the most effective extract by preventing the reduction of MTT by about 80% in the presence of cells 786. Nuclear fragmentation tests showed that this extract induces cell death. The data indicated that mandacaru synthesizes bioactive polysaccharides with potential as antioxidant and antitumor agents. For future studies, it is intended to purify and characterize these polysaccharides and its antioxidant and antitumor mechanisms / A utiliza??o de plantas medicinais para a cura e tratamento de diversas afec??es ? uma pr?tica comum no mundo e tamb?m no Brasil. Em v?rias regi?es do Nordeste brasileiro o cacto Cereus jamacaru, mais conhecido como mandacaru, ? utilizado popularmente no tratamento de v?rias doen?as, incluindo aquelas relacionadas com problemas card?acos, respirat?rios, ?lceras g?stricas, escorbuto, e problemas renais. Contudo, h? uma escassez na literatura cient?fica que comprove cientificamente a aplica??o popular do mandacaru. Assim como outras plantas, Cereus jamacaru sintetiza v?rias mol?culas potencialmente bioativas, como polissacar?deos. Neste trabalho, tr?s extratos aquosos ricos em polissacar?deos, MCA80, MPM e MCP60, foram obtidos dessa planta e analisados quimicamente, bem como, foi avaliado os seus potencias como agentes antioxidantes e citot?xicos. Os dados mostraram que todos os extratos s?o constitu?dos principalmente de polissacar?deos (89,42 a 95,76%), por?m foram detectados contaminantes proteicos (>2 %) e fen?licos (3 a 8,87%). Todos os extratos s?o ricos em galactose, glicose e manose. Al?m disso, de MCA80 e MCP60 apresentam ?cido glucur?nico em sua composi??o. Os extratos apresentaram capacidade antioxidante total variando de 55,21 a 68,13 equivalentes de ?cido asc?rbico (EAA). Por?m n?o apresentaram atividade sequestradora de ?on super?xido. Por outro lado, eles apresentaram atividade redutora e quela??o c?prica de forma dose-dependente. Nenhum dos extratos inibiu a redu??o do MTT na presen?a das c?lulas tumorais de pr?stata (PC-3). Por outro lado, as c?lulas HEK, HeLa e 786 tiveram seu poder redutor de MTT inibido em diferentes n?veis na presen?a dos extratos. MCP60 foi o extrato mais efetivo, impedindo a redu??o do MTT em cerca de 80% na presen?a das c?lulas 786. Ensaios de fragmenta??o nuclear mostraram que esse extrato induz morte celular. Os dados indicaram que mandacaru sintetiza polissacar?deos bioativos com potencial como agentes antioxidantes e antitumorais. Em estudos futuros pretende-se purificar esses polissacar?deos e caracterizar seus mecanismos de a??o antioxidante e antitumoral

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-05-18T11:28:47Z No. of bitstreams: 1 mirelleneryhenrique.pdf: 3757005 bytes, checksum: f81cbf74fa9d4f4e52254d53c930d9aa (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-01T18:23:14Z (GMT) No. of bitstreams: 1 mirelleneryhenrique.pdf: 3757005 bytes, checksum: f81cbf74fa9d4f4e52254d53c930d9aa (MD5) / Made available in DSpace on 2016-07-01T18:23:14Z (GMT). No. of bitstreams: 1 mirelleneryhenrique.pdf: 3757005 bytes, checksum: f81cbf74fa9d4f4e52254d53c930d9aa (MD5) Previous issue date: 2012-03-29 / Este estudo investigou a presença de cândida em manifestações bucais de pacientes com doença renal crônica em pré-diálise, em hemodiálise e em indivíduos saudáveis, utilizando-se de parâmetros clínicos e microbiológicos. Foram selecionados 34 pacientes portadores de doença renal crônica que foram divididos em dois grupos: GE1 – 20 em pré-diálise e; GE2 – 14 em hemodiálise. Para o terceiro grupo (GE3), foram selecionados aleatoriamente 14 indivíduos saudáveis que estavam aguardando atendimento odontológico em clínica particular. Todos os participantes selecionados passaram por uma anamnese e os mesmos responderam a alguns questionamentos sobre a saúde de um modo geral e sobre hábitos particulares de alimentação e hábitos nocivos. A verificação das manifestações bucais foi realizada de forma visual e devidamente fotografada e anotada. Durante o exame intrabucal, nas áreas que apresentavam diagnóstico sugestivo de candidíase, foi coletado material com swab para exame microbiológico, utilizando-se a técnica da Alça Calibrada, onde o meio foi o CHROMagarTM Cândida, para detectar o crescimento de três tipos de cândida: C. albicans, C. krusei e C. tropicalis. Para obtenção dos resultados foi utilizada a prova de Qui-Quadrado, ANOVA (com Post-Hoc LSD) e o teste t de Student, todos com nível de significância de p < 0,05. Das manifestações bucais diagnosticadas, aquela mais frequentemente encontrada foi a “Língua fissurada” com 78,6% no GE2; 60,0% no GE1 e 26,7% no GE3. A “Língua saburrosa” foi a segunda manifestação bucal mais observada, sendo 71,4% no GE2 e 45,0% no GE1. O GE2 foi o grupo que mais apresentou manifestações bucais. Com relação ao diagnóstico visual de candidíase nas manifestações bucais, o GE2 foi prevalente com 28,6%, seguido do GE1 com 25,0%. A C. albicans esteve presente com 17,6% nos pacientes com DRC, sendo 10,0% para o GE1 e 28,6% para o GE2. No GE3 não foi observada a presença de C. albicans. Desta forma, pode-se concluir que nas manifestações bucais observadas, o microrganismo C. albicans esteve presente nos pacientes com doença renal crônica em pré-diálise e hemodiálise, porém sem significância para afirmar que o mesmo seja oportunista para desencadear a candidíase. / This study investigated the presence of oral manifestations of candidiasis in patients with chronic kidney disease in predialysis, hemodialysis and healthy subjects, using the clinical and microbiological parameters. We selected 34 patients with chronic kidney disease who were divided into two groups: EG1 – 20 in pre-dialysis; EG2 – 14 on hemodialysis. For the third group (EG3) were randomly selected 14 healthy subjects who were waiting for dental care in private practice. All selected participants underwent an interview and they answered some questions about health in general and on particular habits of diet and harmful habits. Verification of oral manifestations was performed visually and duly photographed and recorded. During the examination intraoral areas with the diagnosis suggestive of candidiasis, swab material was collected for microbiological examination, using the technique of calibrated loop where the medium was CHROMagarTM Candida, to detect the growth of three types of bleach: C. albicans, C. krusei and C. tropicalis. To obtain the results we used the chi-square test, ANOVA (with post-hoc LSD) and Student's t test, all with a significance level of p < 0.05. Of oral lesions diagnosed, that was the most frequently found "Fissured tongue" with 78.6% in EG2, 60.0% and 26.7% in the EG1 and EG3. The "Tongue furred" was the second most frequent oral manifestation, being 71.4% and 45.0% in the EG2 and EG1. The EG2 was the group that presented oral manifestations. With respect to visual diagnosis of candidiasis in the oral manifestations, the EG2 was prevalent in 28.6%, followed by EG1 with 25.0%. The C. albicans was present in 17.6% in patients with chronic kidney disease, and to GE1 10.0% and 28.6% for EG2. EG3 was not observed in the presence of C. albicans. Thus, it can be concluded that oral manifestations observed in the microorganism C. albicans was present in patients with chronic kidney disease in predialysis and hemodialysis, but no significance to claim that it is opportunistic to trigger candidiasis.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-05-19T13:15:36Z No. of bitstreams: 1 lucianasenradesouzasodre.pdf: 2583041 bytes, checksum: e088ae0b9ebe9783802436c9e53f9a77 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-19T14:45:29Z (GMT) No. of bitstreams: 1 lucianasenradesouzasodre.pdf: 2583041 bytes, checksum: e088ae0b9ebe9783802436c9e53f9a77 (MD5) / Made available in DSpace on 2017-05-19T14:45:29Z (GMT). No. of bitstreams: 1 lucianasenradesouzasodre.pdf: 2583041 bytes, checksum: e088ae0b9ebe9783802436c9e53f9a77 (MD5) Previous issue date: 2017-04-06 / Introdução: A doença de Fabry é uma doença hereditária ligada ao cromossoma X. É um erro inato no metabolismo dos glicoesfingolipídeos. Devido à ausência ou deficiência da Alfagalactosidase A, ocorre acúmulo da globotriasilceramida no tecido dos órgãos, levando à considerável morbimortalidade. A maioria dos estudos faz triagem somente de homens em hemodiálise. Objetivos deste estudo: 1- Avaliar a prevalência da doença de Fabry em centros de diálise no Brasil em homens e mulheres, feita inicialmente com um questionário e, a seguir, com um algoritmo computacional que seleciona os casos suspeitos para coleta de sangue. 2- Observar a presença e importância dos principais sinais e sintomas nos pacientes com doença renal. Métodos: Este estudo consta de uma análise de dados secundária de um projeto multicêntrico denominado: Análise Clínica e Epidemiológica da Doença de Fabry nos Centros de Diálise do Brasil, “Projeto Rim Fabry Brasil”. Foram incluídos no estudo 854 centros de diálise de todo o Brasil. Foi aplicado questionário/algoritmo computacional nos pacientes e após ter-se encontrado os pacientes com a doença de Fabry, seus familiares foram triados. Todos assinaram o Termo de Consentimento Livre e Esclarecido. Depois de aplicado o questionário, esses dados foram digitados em um programa de computador (algoritmo computacional) criado pelo coordenador do estudo. Esse programa/algoritmo computacional separa em descarte, os que provavelmente não têm a doença de Fabry, em suspeitos, os que foram encaminhados para coleta de sangue e análise. Quando detectados pacientes suspeitos, esses tiveram sangue coletado em papel filtro para dosagem enzimática e teste genético. Foi realizada uma análise descritiva dos dados e razão de verossimilhança entre os sintomas de pacientes com doença de Fabry e doença renal vs pacientes com doença de Fabry sem doença renal. Foi realizado também a razão de verossimilhança nos grupos de análise vs descartados, coleta vs descartados e positivos vs negativo. Resultados: Foram triados 36442 indivíduos com doença renal e encontrados 71 pacientes com doença de Fabry. Foram pesquisados 1214 indivíduos entre os familiares dos pacientes positivos com a doença renal e encontrados mais 115 indivíduos com doença de Fabry. Somaram-se então 37656 pacientes, sendo 28284 descartados e 9301 encaminhados para análise, encontrados 186 positivos no total da amostra. A prevalência de doença de Fabry na população com doença renal foi de 0,19% antes do questionário e algoritmo computacional e, depois de aplicados, foi de 0,87%. Entre os familiares foi de 9,47%. Na população total do estudo foi de 0,49% e, naqueles triados pelo algoritmo computacional, 2,24%. Houve maior prevalência de mulheres (65,1%), apesar de terem sido triados mais homens (59,3%). Foram separados dois grupos: doença de Fabry com doença renal (n=71) e doença de Fabry sem doença renal (n=115). Com relação aos sinais e sintomas e as comorbidades, foram mais frequentes as doenças reumatológicas (71,8%) seguida das doenças cardíacas (60,6%), diminuição ou ausência da transpiração (42,3%), hipertensão arterial (35,2%), depressão (28,2%), intolerância ao calor e ao frio (28,2%), crises de dor que se espalham pelo corpo (26,8%), doenças neurológicas (25,4%), sensação de queimação nas mãos e nos pés (23,9%), sensação de dormência nas mãos e pés (22,5%), e febre recorrente (16,9%) naqueles com doença renal. Conclusão: Encontramos uma prevalência próxima à descrita na literatura, quando não considerado o questionário e o algoritmo computacional. Considerando o questionário e o algoritmo computacional, a prevalência sobe em toda população triada, incluindo os familiares. Quando considerado somente a população com doença renal, a prevalência é de 0,19% antes do questionário e algoritmo computacional e de 0,87%, depois do questionário e algoritmo computacional. Nos familiares dos pacientes com doença de Fabry a prevalência foi de 9,47%. Na população total do estudo foi de 0,49% antes do questionário e algoritmo computacional e de 2,24% depois do questionário e algoritmo computacional. Encontramos também maior prevalência de casos da doença de Fabry, no gênero feminino. Percebemos que o grupo com doença renal apresenta mais sinais e sintomas da doença de Fabry que o grupo sem doença renal. Acreditamos que o uso do algoritmo computacional aumenta a sensibilidade do questionário, possibilitando o diagnóstico de um maior número de casos, restringindo a análise laboratorial a casos de maior risco. / Introduction: Fabry disease is an inherited disease linked to the X chromosome. It is an innate error in the metabolism of glycosphingolipids. Due to the absence or deficiency of α galactosidase A, accumulation of globotriasylceramid occurs in the tissues, leading to considerable morbidity and mortality. Most of the studies only evaluated men on hemodialysis. Objectives: 1- To evaluate the prevalence of Fabry disease in dialysis centers in Brazil in males and females, initially used a questionnaire and then an computational algorithm that selects the suspected cases for blood collection. 2- To evaluate the presence and importance of the main signs and symptoms in these kidney disease patients. Methods: This study is a secondary data analysis from a multicentric project: Clinical and Epidemiological Analysis of Fabry Disease in Brazilian Dialysis Center: “Brazil Fabry Kidney Project”. The study included 854 dialysis centers throughout Brazil. Patients and family who signed the Informed Consent Term were evaluated. After the questionnaire was applied to the patient, this data was entered into a computerized system. This algorithm separates into discard, those who probably do not have Fabry's disease, into suspects, those who were referred for blood collection and analysis, and those who the system had doubts about and needs the intervention of program creators to decide whether to collect. When detected suspect patients, they had blood collected on filter paper for enzymatic dosing and genetic testing. A descriptive analysis of the data was performed, the likelihood ratio between the symptoms of Fabry disease patients and with kidney disease vs Fabry disease without kidney disease. The likelihood ratio was also performed in the groups of analysis vs discard, collection vs discard and positive vs negatives. Results: 36442 individuals with kidney disease were screened and 71 patients with Fabry disease were found. Searched 1214 individuals among the relatives of the positive patients and found another 115 individuals with Fabry. There were 37656 patients, 28284 of which were discarded and 9301 referred for analysis. Of them, 186 were positive in the total sample. The Fabry disease prevalence in the population with kidney disease was 0.19% before the questionnaire and the algorithm were used and 0.87% after. Among the relatives was 9.47%. In the total population of the study was 0.49% and in those screened by the algorithm, 2.24%. There was a higher prevalence of women (65.1%), although more men were screened (59.3%). Two groups were separated: Fabry disease with kidney disease (71) and Fabry disease without kidney disease (115). Regarding signs, symptoms and comorbidities, rheumatologic diseases were more frequent (71.8%) followed by heart disease (60.6%), decrease or absence of sweating (42.3%), arterial hypertension (35.2%), depression (28.2%), intolerance to heat and cold (28.2%), pain crises that spread through the body (26.8%), neurological diseases (25.4%), burning sensation in the hands and feet (23.9%), numbness sensation in the hands and feet (22.5%), and recurrent fever (16.9%) in those with kidney disease. Conclusion: We found prevalence close to that described in the literature, when the questionnaire and the algorithm were not used. Using the questionnaire and the algorithm, prevalence rises in all screening population including family members. Considering only the population with kidney disease the prevalence was 0.19% before the questionnaire and algorithm were used and 0.87%, after the questionnaire and algorithm. In the relatives of Fabry disease patients, the prevalence was 9.47%. In total study population was 0.49% before using the questionnaire and algorithm and 2.24% after that. We also found a higher prevalence of the Fabry disease in females. We noticed that the group with kidney disease has more signs and symptoms. We believe that the use of the algorithm increases the sensitivity of the questionnaire, allowing the diagnosis of a greater number of cases, restricting the laboratory analysis to cases of greater risk.

Philosophiae Doctor - PhD / End stage renal disease (ESRD), a more severe form of kidney disease, is considered to be a complex trait that may involve multiple processes which work together on a background of a significant genetic susceptibility. Black Africans have been shown to bear an unequal burden of this disease compared to white Europeans, Americans and Caucasians. Despite this, most of the genetic and epidemiological advances made in understanding the aetiology of kidney diseases have been done in other populations outside of sub-Saharan Africa (SSA). Very little research has been undertaken to investigate key genetic factors that drive ESRD in Africans compared to patients from rest of world populations. Therefore, the primary aim of this Bioinformatics thesis was twofold: firstly, to develop and apply a whole exome sequencing (WES) analysis pipeline and use it to understand a genetic mechanism underlying ESRD in a South African population of mixed ancestry. As I hypothesized that the pipeline would enable the discovery of highly penetrate rare variants with large effect size, which are expected to explain an important fraction of the genetic aetiology and pathogenesis of ESRD in these African patients. Secondly, the aim was to develop and set up a multicenter clinical database that would capture a plethora of clinical data for patients with Lupus, one of the risk factors of ESRD. From WES of six family members (five cases and one control); a total of 23 196 SNVs, 1445 insertions and 1340 deletions, overlapped amongst all affected family members. The variants were consistent with an autosomal dominant inheritance pattern inferred in this family. Of these, only 1550 SNVs, 67 insertions and 112 deletions were present in all affected family members but absent in the unaffected family member. Following detailed evaluation of evidence for variant implication and pathogenicity, only 3 very rare heterozygous missense variants in 3 genes COL4A1 [p.R476W], ICAM1 [p.P352L], COL16A1 [p.T116M] were considered potentially disease causing. Computational relatedness analysis revealed approximate amount of DNA shared by family members and confirmed reported relatedness. Genotyping for the Y chromosome was additionally performed to assist in sample identity. The clinical database has been designed and is being piloted at Groote Schuur medical Hospital at the University of Cape Town. Currently, about 290 patients have already been entered in the registry. The resources and methodologies developed in this thesis have the potential to contribute not only to the understanding of ESRD and its risk factors, but to the successful application of WES in clinical practice. Importantly, it contributes significant information on the genetics of ESRD based on an African family and will also improve scientific infrastructure on the African continent. Clinical databasing will go a long way to enable clinicians to collect and store standardised clinical data for their patients.

La néphropathie à IgA (IgAN), est une maladie glomérulaire chronique primitive et principale cause d'insuffisance rénale dans le monde. Les causes et les facteurs aboutissant aux dépôts des complexes d'IgA1 sont inconnus. La forme soluble du récepteur (CD89s) complexée aux IgA joue un rôle clé dans la pathogenèse de cette maladie. Actuellement, aucun traitement spécifique n'est disponible et les options thérapeutiques sont limitées. La compréhension des mécanismes de la formation de ces complexes permettra d'envisager de nouvelles approches thérapeutiques. Dans cette perspective la première partie de cette thèse, met en évidence l'implication d'une protéine essentielle au développement de la N-IgA, la TG2, dans la régulation du clivage du CD89, et cela par la répression de la sérine phosphatase PP2A et l'activation de la métalloprotéase matricielle MMP-9. Dans les monocytes de patients l'expression diminuée de PP2A est associée à une tendance à l'augmentation de TG2, et inversement corrélée avec l'augmentation des complexes IgA1-CD89s. Afin de cibler ces complexes pathogéniques, un essai préclinique a été réalisé avec une protéase recombinante d'origine bactérienne clivant spécifiquement les IgA1 (IgA1-P). Les résultats ont formellement démontré la spécificité et l'efficacité de la protéase dans la réduction des complexes circulants et des dépôts d'IgA1 dans le modèle humanisé de N-IgA, associée à une diminution des marqueurs de l'inflammation et de l'hématurie. Les résultats ont mis en évidence le rôle de la dérégulation de l'axe TG2-PP2A-MMP-9 dans la formation des complexes IgA1-CD89s lors de la N-IgA, ainsi que l'efficacité de l'IgA1-P à éliminer ces complexes. Ces travaux suggèrent en plus du potentiel thérapeutique promoteur de l'IgA1-P, trois éventuelles cibles thérapeutiques envisageables pour la N-IgA. / IgA nephropathy (IgAN) is a mesangial proliferative primary glomerulonephritis and a major cause of end-stage renal disease. Causes and factors leading to mesangial IgA1 deposition are unknown. The soluble form of the receptor (sCD89) complexed with IgA plays a key role in the pathogenesis of the disease. There is currently no specific treatment available and the therapeutic options are limited. A better comprehension of the mechanisms regulating the formation of IgA1-sCD89 complexes will unveil new strategies for targeted therapies. In this perspective, the first part of this thesis highlights the implication of the transglutaminase 2 (TG2), a protein essential for the development of IgAN, in the regulation of CD89 cleavage, in a mechanism involving the repression of the serine phosphatase PP2A and the activation of the matrix metalloproteinase MMP-9. While a trend towards TG2 increase is observed, PP2A expression is reduced in monocytes obtained from IgAN patients compared to controls, and inversely correlates with the levels of circulating hIgA1-sCD89 complexes. In order to target these pathogenic complexes, a preclinical assay has been performed with a recombinant protease, a bacterial protein that selectively cleaves human IgA1 (IgA1-P). Results formally demonstrate the specificity and the efficacy of the IgA1-P in the reduction of circulating complexes and mesangial IgA1 deposition in a humanized mouse model of IgAN, associated with a reduction in inflammation and hematuria. Concluding, the results presented in this thesis show a role for the TG2-PP2A-MMP-9 axis in the dysregulated formation of IgA1-sCD89 complexes during IgAN development, as well as the effectiveness of IgA1-P in the elimination of these complexes. In addition to the potential therapeutic use of IgA1-P, this work suggests the TG2-PP2A-MMP-9 axis as a new therapeutic candidate for IgAN treatment.

Introduction Severe hypercalcemia from chronic gout is a rare phenomenon seen after the advent of newer drugs for its treatment. The hypercalcemia is secondary to either granuloma formation around the tophi or chronic immobilization from severe gouty arthritis. We present a patient with chronic tophaceous gout presenting with severe hypercalcemia and acute kidney injury. Case presentation A 63-year-old male patient with a past medical history of hypertension and chronic gout presented to the office with chronic, severe left knee pain. Initial evaluation of the knee with X-rays revealed destruction of the knee joint with cystic changes, and subsequent MRI with contrast showed soft tissue mass in the suprapatellar pouch with intraosseous extension and involvement of medial and lateral collateral ligament involvement. After interdisciplinary evaluation between radiology, orthopedic surgery, and oncology, this was concerning for highly aggressive pigmented villonodular synovitis of the knee, and a decision was made for the patient to undergo complete knee replacement. Perioperative workup was significant for severe hypercalcemia with a total calcium level of 13.2 mg/dl with ionized calcium of 7.2 mg/dl. Further evaluation into the cause of hypercalcemia revealed a low normal intact parathyroid hormone (PTH) level with normal phosphorus, calcidiol, and calcitriol levels. Other etiologies of hypercalcemia such as multiple myeloma, malignancies, metastatic disease, autoimmune, granulomatous, and infectious processes are excluded with extensive workup. The hypercalcemia is treated with fluids, diuretics, and bisphosphonates, eventually normalizing the calcium levels. The patient underwent total left knee replacement, and the mass identified was sent for biopsy. Biopsy revealed a prominent granulomatous reaction to amorphous crystals containing birefringent crystals under polarised light. Uniquely during our evaluation, vitamin D metabolites, uric acid, and PTH levels were normal despite the biopsy findings. The patient's calcium continued to be normal (8.4 to 10.4 mg/dl) over six months after the surgery. Thus, the scenario is supportive of hypercalcemia secondary to granulomatous inflammation around the large tophi. Conclusion Although rare, the knee joint is a site of severe tophaceous gout, and deposition of uric acid crystals can invoke a granulomatous reaction presenting with severe hypercalcemia as in our patient. Unique to our case, the patient can have benign lab findings on evaluation of hypercalcemia. Only a few case reports are illustrated in the literature, making our case and patient presentation unique.

A doença renal policística autossômica dominante (DRPAD) constitui-se na enfermidade humana monogênica com risco de óbito mais frequente, responsabilizando-se por 4,4 a 10,0% dos casos de doença renal terminal em diferentes populações. Na quase totalidade dos pacientes, a doença é causada por mutação em um de dois genes: PKD1 (polycystic kidney disease 1) ou PKD2 (polycystic kidney disease 2). Tais genes codificam, respectivamente, as proteínas policistina-1 (PC1) e policistina-2 (PC2). Mutações em PKD1, por sua vez, respondem pela ampla maioria dos casos de DRPAD. Camundongos haploinsuficientes para Pkd1 (Pkd1+/-), o gene ortólogo a PKD1 neste animal, consistem num modelo não cístico de deficiência de atividade deste gene. Em um estudo anterior, mostramos que animais Pkd1+/- apresentam lesão renal mais severa que camundongos selvagens (Pkd1+/+) quando submetidos a isquemia/reperfusão (I/R) renal. Esse estudo sugeriu, portanto, que a capacidade de regeneração renal pós-I/R esteja prejudicada em camundongos Pkd1+/- e em pacientes com DRPAD. O insulto por I/R constitui-se em uma causa importante de indução de estresse de retículo endoplasmático (ER), podendo ativar as vias UPR (unfolded protein response) e ERAD (ER-associated degradation). Além disso, a ativação de vias envolvidas no ER determinado por I/R exerce um efeito de agravamento da lesão decorrente deste insulto. O ER pode, ainda, ativar e ser induzido pela resposta inflamatória. Estudos prévios revelaram que as policistinas também se relacionam com este processo. A expressão de PC2 pode ser superregulada pela ativação de um dos braços da via UPR, enquanto a ativação da via ERAD estimula sua degradação. A superexpressão de XBP1, por sua vez, atenua o fenótipo cístico em camundongos deficientes em Pkd1, revelando que a ativação da via UPR pode mitigar a formação cística. Para analisar a relação entre ER e suscetibilidade aumentada a I/R na deficiência de Pkd1, avaliamos diferentes marcadores de ER em camundongos Pkd1+/- e Pkd1+/+ submetidos a um insulto leve por I/R renal associado a 32 min de isquemia. A razão de expressão renal dos mRNAs Xbp1s/Xbp1u mostrou-se menor em camundongos Pkd1+/- que Pkd1 +/+ 48 h após I/R, enquanto a expressão proteica de XBP1s foi maior em rins Pkd1+/- comparados a Pkd1+/+ após o insulto. Não detectamos diferença na expressão renal do gene Hspa5 e de seu produto BIP/GRP78, assim como na expressão de Ddit3, gene que codifica CHOP, após intervenção sham e após I/R. Também não observamos diferenças entre os níveis renais e séricos de IL1beta, IL6, IL10, TNFalfa e RANTES entre camundongos Pkd1+/- e Pkd1+/+ pós-procedimento sham e pós-I/R, embora tendências não significantes de elevação de MCP1 tenham sido detectadas nos rins submetidos ao insulto para ambos os genótipos. As variações em sentidos opostos de XBP1s e Xbp1s/Xbp1u determinadas por I/R em rins Pkd1+/- são consistentes com uma maior suscetibilidade destes animais à indução de ER. Esses achados sugerem que a indução de ER em resposta a um insulto leve por I/R possa aumentar a atividade de PC1 e exercer um efeito de atenuação sobre a maior suscetibilidade de camundongos deficientes em Pkd1 a I/R renal / Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening monogenic disease in humans, accounting for 4.4 to 10.0% of the end-stage kidney disease cases in different populations. In almost all patients, this disorder is caused by a mutation in one of two genes: PKD1 (polycystic kidney disease 1) or PKD2 (polycystic kidney disease 2). These genes encode, respectively, the proteins polycystin-1 (PC1) and polycystin-2 (PC2). Mutations in PKD1, in turn, are responsible for the large majority of ADPKD cases. Pkd1- haploinsufficient mice (Pkd1+/-), the gene orthologous to PKD1 in this animal, constitute a noncystic model of this gene\'s deficiency. In a previous study, we showed that Pkd1+/- animals develop a more severe renal injury than wild-type mice (Pkd1+/+) when submitted to renal ischemia/reperfusion (I/R). This study suggested, therefore, that the capacity of renal regeneration following I/R is impaired in Pkd1+/- mice and in ADPKD patients. The I/R insult is an important cause of endoplasmic reticulum stress (RS) induction, potentially leading to activation of the UPR (unfolded protein response) and ERAD (ER-associated degradation) pathways. The activation of pathways involved in RS determined by I/R exerts an aggravating effect on the injury resulting from the insult. In addition, RS can activate and be induced by the inflammatory response. Previous studies revealed that polycystins also relate to this process. PC2 expression can be upregulated by the activation of one of the UPR pathway branches, while activation of the ERAD pathway stimulates its degradation. XBP1 overexpression, in turn, attenuates the cystic phenotype in Pkd1-deficient mice, revealing that activation of UPR can mitigate cyst formation. To analyze the relationship between RS and the increased susceptibility to I/R associated to Pkd1 deficiency, we evaluated different RS markers in Pkd1+/- and Pkd1+/+ mice submitted to a mild I/R insult determined by 32-min ischemia. The renal expression ratio of mRNA Xbp1s/Xbp1u was lower in Pkd1+/- than Pkd1+/+ mice 48 h after I/R, while the XBP1s protein expression was higher in Pkd1+/- compared to Pkd1+/+ kidneys after the insult. We have not detected differences in renal expression of the Hspa5 gene and its product BIP/GRP78, as well as in Ddit3 expression, the gene that encodes CHOP, postsham intervention and post-I/R. We have also not observed differences in the renal and serum levels of IL1beta, IL6, IL10, TNFalfa and RANTES between Pkd1+/- e Pkd1+/+ mice post-sham procedure and post-I/R, although non-significant trends of MCP1 increase have been detected in kidneys submitted to the insult for both genotypes. The variations in different directions of XBP1s and Xbp1s/Xbp1u induced by I/R in Pkd1+/- kidneys are consistent with a higher susceptibility of these animals to RS induction. These findings suggest that the RS induction in response to a mild I/R insult can increase PC1 activity and exert an attenuating effect on the increased susceptibility of Pkd1-deficient mice to renal I/R