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Thesis (M.S.)--Ohio State University, 2008. / Title from first page of PDF file. Includes bibliographical references (p. 75-100).

Indiana University-Purdue University Indianapolis (IUPUI) / Heritable disorders of phosphate handling are the most common cause of hypophosphatemic rickets in developed countries. Isolated renal phosphate wasting and subsequent low serum phosphate concentrations may result from a number of genetic disorders that include: autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), and autosomal recessive hypophosphatemic rickets (ARHR). Fibroblast growth factor-23 (FGF23), identified as the causative gene in ADHR, is produced in bone and plays a central role in kidney phosphate regulation. Increased serum concentrations of FGF23 lead to renal phosphate wasting through down regulation of renal sodium-phosphate co-transporters. However, the molecular mechanisms of FGF23 bioactivity in hormonal phosphate regulation are largely unknown. An experimental focus of this dissertation was to investigate the molecular mechanisms of FGF23-mediated phosphate regulation in the bone-kidney hormonal axis. To this end, the role of Dentin Matrix Protein 1 (DMP1), newly identified as the gene responsible for ARHR, was further defined by the identification of a novel large deletion as well as testing the molecular consequences of DMP1 mutations. FGF23 requires a signaling complex composed of Klotho and an FGFR for bioactivity, however, the location and composition of the signaling complex is unknown. Klotho localizes to the renal distal convoluted tubule, whereas the sodium phosphate co-transporters are expressed within the renal proximal tubules. The molecular mechanisms of FGF23 signaling were investigated by isolating a novel marker of FGF23 bioactivity using array technology, determining the location of initial FGF23 signaling in the kidney, and by identifying a novel mutation in a receptor upstream of FGF23 production. Taken together, these results increase the knowledge of the molecular mechanisms of phosphate homeostasis in relation to FGF23 bioactivity, leading to the identification of potentially novel therapeutic targets. / indefinitely

Vitamin D deficiency at Middenbeemster and Hattem is the result of cultural variables that limit an individual’s exposure to sunlight. During growth spurts, such as the pubertal growth spurt, high demand for vitamin D puts individuals at an increased risk for developing conditions such as rickets. This thesis aims to determine whether adolescent rickets can be identified in archaeological skeletal remains, and how to quantify the observed changes. The current work also aims to use the prevalence of adolescent rickets to understand the underlying social changes affecting individuals in the Netherlands in the 17th to 19th centuries. Two collections of archaeological human remains from the 17th to 19th century Dutch sites of Middenbeemster (n=246) and Hattem (n=117) were evaluated using macroscopic, metric, radiographic, and micro-CT analysis of skeletal remains. Adolescent individuals were evaluated for signs of active adolescent rickets, and adults were evaluated for signs of residual adolescent rickets. Statistical analysis found that measurements quantifying shape changes at the distal ulna, medial clavicle, and sacral angle can be used to identify adolescent rickets in a skeletal sample. Adolescent rickets at Middenbeemster and Hattem was found to be distributed equally amongst males and females and was found to occur less frequently than rickets in infants and children from the same population. Rickets in adolescents was most likely caused by the onset of new jobs or roles resulting in individuals remaining indoors for long periods of time. Rickets may have also been caused by illness. By identifying rickets in adolescents, this thesis provides a window to view the changing roles of individuals as they begin to occupy new spaces in their transition from children into adults, thus providing a novel way to investigate the lives of adolescents. / Thesis / Master of Arts (MA)

Vitamin D is a fat-soluble hormone primarily responsible in maintaining plasma calcium and phosphorus homeostasis in humans. Vitamin D insufficiency and deficiency is a global health issue. Very few foods naturally contain vitamin D; a major source is oily fish such as salmon. Several studies have analyzed vitamin D content in various fish, however studies concerning canned fish are lacking. In particular, this study was interested in evaluating the vitamin D content in canned sardines in not only the whole fish but also in the olive oil or water it was canned in. It was hypothesized that the vitamin D content in sardines canned in water would be greater than sardines canned in olive oil due to the fat-soluble nature of vitamin D to be more easily extracted into olive oil than water. Sardines (~100g) canned in olive oil had a slightly greater vitamin D content than the sardines in water (2,555.6±234.2 and 1,993.7±2,411.3 IUs (p<0.05) respectively). An evaluation of the vitamin D3 content in the olive oil and water used to can the sardines revealed 701.4±471.1 and 149.1±42.2 IUs in the total olive oil and water respectively recovered from the cans. It was determined that of the total vitamin D content in the can (sardines in olive oil or water) 20.9%±12.8% of vitamin D3 is found in the olive oil compared to only 14.2%±10.4% (p<0.05) vitamin D3 found in water. These results support the concept that sardines packed in olive oil may have less vitamin D3 than similar sardines packed in water. The analysis of the sardines revealed that they had more than 13 times the amount of vitamin D3 than that is reported in the USDA table of nutritional facts for canned sardines. This could be because the sardines were caught in the summer months when they are more likely to be consuming food containing vitamin D3 as a result of reduced synthesis of vitamin D3 in zooplankton and other lower life forms that the sardines consume. An alternative explanation for this increase in vitamin D3 content is the process of canning the sardines. Vital Choice, the supplier of the sardines, immediately ices the fish upon retrieval from the ocean (to ensure freshness) and then are canned in less than 5 hours after being caught. This process of freshness preservation could explain why the vitamin D content was so high; possibly an accurate representation of the original vitamin D content in the sardines.

Recognising that NPT2 is the major Na/Pi cotransporter in the kidney, that hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by a renal Pi leak and, that Npt2 knockout mice demonstrate a biochemical phenotype similar to that of patients with HHRH, we sought to determine whether NPT2 was a candidate gene for this disorder. Using single-strand conformation polymorphsim (SSCP) analysis and sequencing in six unrelated pedigrees with the disease, we found no disease-causing mutations. Two polymorphisms were identified in the gene and used as markers to examine segregation of NPT2 with the disease. HHRH did not segregate with the gene markers. In addition, the impact of NPT2 on bone mineral density (BMD) was examined by genotyping a population of 104 individuals for which BMD data was available, and determining whether there was an association between NPT2 genotype and bone density. No significant association was found between NPT2 genotype and BMD.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1935. / Typescript. With this are bound: The effect of feeding high amounts of soluble iron and aluminum salts / H.J. Deobald and C.A. Elvehjem. Reprinted from American journal of physiology, vol. 111, no. 1 (Feb. 1935), p. 118-123 -- Availability of calcium salts for chicks / by H.J. Deobald, C.A. Elvehjem, E.B. Hart, and J.G. Halpin. Reprinted from Poultry science, vol. XV, no. 1 (Jan. 1936), p. 42-47. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / X-linked hypophosphatemic rickets (XLHR) is the most common cause of heritable rickets, with an incidence of 1:20,000 live births, representing more than 80% of familial hypophosphatemic rickets. Saliva is the most easily available and accessible body fluid, which makes it one of the most sought after tools in diagnostic pathology. In this context, this thesis, constituted by 4 articles aimed to: (1) describe the main systemic manifestations, oral findings and dental management in 3 generations of an affected family; (2) analyze the mineralization pattern of enamel and dentin in patients affected by XLHR using micro-CT, and to associate enamel and dentin mineralization in primary and permanent teeth with tooth position, gender and presence/absence of this disease; (3) evaluate the peptide profile in the saliva of patients with X-linked hypophosphatemic rickets using high performance liquid chromatography; and (4) characterize salivary proteins in this condition using unidimensional electrophoresis. On study 1, oral exams, laboratorial and histologic evaluations, cone-beam computed tomographies, panoramic and periapical radiographs were performed to properly institute the most adequate treatment strategy. On study 2, teeth were collected from 5 individuals from the same family. Gender, age, tooth position (anterior/posterior) and tooth type (deciduous/permanent) were recorded for each patient. Following collection, teeth were placed in 0.1% thymol solution until Micro-CT scan. Projection images were reconstructed and analyzed. On study 3, unstimulated whole and stimulated parotid saliva were obtained from 8 individuals with (AFF) and 8 healthy individuals, both genders, without (CON) x-linked hypophosphatemic rickets aged from 8 to 66 years. Supernatants were analyzed by high performance liquid chromatography, and the salivary flow rate (ml/min) was calculated. Each major peak in the HPLC chromatogram of each sample was characterized. On study 4, unstimulated whole and stimulated parotid saliva were also obtained, being total protein concentration determined by the Bicinchoninic Acid Protein (BCA) method. Proteins were characterized according to their molecular weights within the unidimensional electrophoresis. The study 1 showed the importance of the knowledge of clinical signs and symptoms of XLHR for the correct diagnosis of this disease, and for the establishment of preventive and comprehensive dental care. On article 2, teeth of all affected patients presented dentin with a different mineralization pattern compared to the teeth of the healthy individual with dentin defects observed next to the pulp chambers. On the third article, whole and parotid salivary flows were significantly different (p = 0.001), being flow of whole saliva higher (0.518  0.282 mL/min) than parotid saliva (0.124  0.086 mL/min). Whole salivary flow rate was higher in the AFF group (0.698  0.229) than in the CON group (0.339  0.210 mL/min) (p = 0.006). Twenty-eight peaks were found in whole and 21 peaks in parotid saliva. Whole saliva of the CON group presented lower number of peaks than AFF group. In parotid saliva, peaks 17 and 28 (retention times: 24 and 39 min) were found exclusively in the AFF group, and peak 13 (retention time: 19 min) exclusively in the CON. Article 4 showed difference concerning to total protein concentration between whole and parotid saliva (p < 0.001), being higher concentration found in whole saliva (102.603  42.336 Âg/mL) than in parotid saliva (0.699  0.438 Âg/mL). Bands with 102 kDa, 48 kDa and 24 kDa presented higher intensity in whole saliva of CON group (p = 0.015, p = 0.043 and p = 0.022). In conclusion, XLHR patients presented specific characteristics in dentin mineralization and salivary proteins and peptides, which can lead to differentiate these patients from healthy individuals, improving the diagnostic field. / Raquitismo hipofosfatÃmico ligado ao cromossomo X (XLHR) à a maior causa de raquitismo hereditÃrio, com uma incidÃncia de 1:20.000 nascidos vivos, representando mais de 80% das formas de raquitismo hipofosfatÃmico familiar. A saliva à o fluido humano mais disponÃvel e de fÃcil acesso, o que faz dela uma das ferramentas mais pesquisadas no diagnÃstico de patologias. Nesse contexto, essa tese, constituÃda de 4 artigos objetivou: (1) descrever as principais manifestaÃÃes sistÃmicas, achados orais e tratamentos dentÃrios em 3 geraÃÃes de uma famÃlia afetada; (2) analisar o padrÃo de mineralizaÃÃo do esmalte e da dentina nos pacientes afetados por XLHR, utilizando microtomografia computadorizada (Micro CT), e associar a mineralizaÃÃo do esmalte e da dentina em dentes decÃduos e permanentes, segundo gÃnero e presenÃa/ausÃncia da doenÃa; (3) avaliar o perfil de peptÃdeos na saliva de pacientes com XLHR, utilizando cromatografia lÃquida de alta performance (HPLC); e (4) caracterizar proteÃnas salivares nessa condiÃÃo, utilizando eletroforese unidimensional. No estudo 1, exames orais, laboratoriais e avaliaÃÃes histolÃgicas, tomografias computadorizadas cone-beam e radiografias periapicais foram realizadas para a apropriada instituiÃÃo da estratÃgia de tratamento mais adequada. No estudo 2, dentes foram coletados de 5 indivÃduos de uma mesma famÃlia. GÃnero, idade, posiÃÃo dentÃria (anterior/posterior) e tipo dentÃrio (decÃduo/permanente) foram registrados para cada paciente. ApÃs a coleta, os dentes foram colocados em soluÃÃo de timol a 0,1% atà a anÃlise atravÃs do Micro CT. As imagens projetadas foram reconstruÃdas e analisadas. No estudo 3, saliva total nÃo estimulada e saliva de parÃtida estimulada foram obtidas de 8 indivÃduos afetados com (AFF) e 8 indivÃduos sem (CON) XLHR, de ambos os gÃneros e idades entre 8 e 66 anos. Sobrenadantes foram analisados por meio de HPLC e o fluxo salivar (mL/min) foi calculado. Os picos que se apresentaram maiores nos cromatogramas do HPLC foram caracterizados. No estudo 4, saliva total nÃo estimulada e saliva de parÃtida estimulada tambÃm foram obtidas, sendo a concentraÃÃo de proteÃnas totais determinada pelo MÃtodo do Ãcido BicinconÃnico (BCA). ProteÃnas foram caracterizadas de acordo com o peso molecular atravÃs de eletroforese unidimensional. O estudo 1 mostrou a importÃncia do conhecimento dos sinais e sintomas clÃnicos do XLHR para o correto diagnÃstico dessa doenÃa, e para o estabelecimento de atendimento odontolÃgico preventivo e abrangente. No artigo 2, os dentes de todos os pacientes afetados apresentaram dentina com padrÃo de mineralizaÃÃo diferente comparado aos dentes de indivÃduos saudÃveis, sendo os defeitos na dentina observados prÃximo Ãs cÃmaras pulpares. No artigo 3, os fluxos salivares da saliva total e de parÃtida foram significativamente diferentes (p=0,001), sendo o fluxo de saliva total maior (0,518  0,282 mL/min) do que o de saliva de parÃtida (0,124  0,086 mL/min). O fluxo salivar da saliva total foi maior no grupo AFF (0,698  0,229) que no grupo CON (0,339  0,210 mL/min) (p = 0,006). Vinte e oito picos foram encontrados em saliva total e 21 em saliva de parÃtida. A saliva total do grupo CON apresentou menor nÃmero de picos que a do grupo AFF. Na saliva de parÃtida, os picos 17 e 28 (tempos de retenÃÃo: 24 e 39 min) foram encontrados exclusivamente no grupo AFF e o pico 13 (tempo de retenÃÃo: 19 min) no CON. Artigo 4 demonstrou diferenÃa relacionada à concentraÃÃo de proteÃnas totais entre saliva total e de parÃtida (p < 0,001), sendo a maior concentraÃÃo encontrada na saliva total (102,603  42,336 Âg/mL) que na saliva de parÃtida (0,699  0,438 Âg/mL). Bandas com 102 kDa, 48 kDa e 24 kDa apresentaram maior intensidade na saliva total do grupo CON (p = 0,015, p = 0,043 e p = 0,022). Em conclusÃo, pacientes com XLHR apresentaram caracterÃsticas especÃficas relacionadas à mineralizaÃÃo dentinÃria e proteÃnas e peptÃdeos salivares que podem levar à diferenciaÃÃo desses pacientes de indivÃduos saudÃveis, avanÃando no campo diagnÃstico.

Orientador: Lilia F. R. de Souza Li / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T11:10:27Z (GMT). No. of bitstreams: 1 Macedo_LuciaCosentinode_M.pdf: 2481805 bytes, checksum: 85ab094926dbe8ad65a47ec2c1c6fcf5 (MD5) Previous issue date: 2006 / Resumo: A 1,25-dihidroxivitamina D é de fundamental importância na homeostase do cálcio. A vitamina D exerce suas ações através da interação com o seu receptor. O receptor da vitamina D (VDR) é membro da superfamília de receptores nucleares. O raquitismo é uma doença causada por mineralização deficiente na matriz óssea ou osteóide, afetando o desenvolvimento e a formação do osso na fase de crescimento. Mutações no receptor da vitamina D causam raquitismo dependente de vitamina D tipo II. Neste tipo de raquitismo ocorre hipocalcemia e as concentrações séricas de 1,25-dihidroxivitamina D3 são elevadas e, na maioria das vezes não há resposta ao tratamento com doses altas de 1,25-dihidroxivitamina D. Pacientes apresentam raquitismo grave de inicio precoce, nos primeiros meses de vida e a maior parte dos indivíduos apresenta pouco ou nenhum pêlo corporal (alopecia). O objetivo principal deste projeto foi a análise molecular do receptor de vitamina D (VDR) em quatro pacientes com raquitismo dependente de vitamina D tipo n que manifestaram raquitismo e alopecia. Amostras de DNA destes pacientes foram usadas para sequenciar o gene do VDR. Os cromatogramas gerados foram analisados em programas específicos, visando a busca de mutações. A análise mostrou 2 novas mutações pontuais que resultam em mudança de aminoácido (Q259E e G319V) e uma mutação que introduz um codon terminal (R73X). A cultura primária de fibroblasto proveniente de biópsia de pele dos pacientes foi usada para análise funcional do receptor. Extrato proteico nuclear mostrou redução de expressão de todos os receptores mutados. O receptor truncado contendo apenas parte do domínio de ligação com o DNA perdeu o epítopo de interação com o anticorpo usado, não sendo identificado no Western blot pelo anticorpo utilizado, impossibilitando a avaliação de sua expressão. Tratamento da cultura primária de fibroblasto com doses crescentes de l,25(OH)2 vitamina D demonstrou que os VDRs mutados foram incapazes de ser ativado e aumentar a expressão de 24-hidroxilase. Este trabalho identificou mutações em quatro pacientes com raquitismo dependente de vitamina D tipo II e estas mutações resultaram em comprometimento funcional do VDR / Abstract: The 1,25-dihydroxyvitamin D plays a fundamental role in the calcium homeostasis. The vitamin D exerts its actions through the interaction with its receptor. The vitamin D receptor (VDR) is a member of the superfamily of nuclear receptors. Rickets is a disease caused by deficient mineralization in the bone matrix or osteoids, affecting the development and formation of the bone during the growth stage. Mutations in the vitamin D receptor are associated to the vitamin D-dependent rickets type II. The biochemical characteristics is hypocalcemia and increase levels of 1,25-dihydroxyvitamin D3, and most of time there is no answer to the treatment with high doses of 1,25-dihydroxyvitamin D. Patients present rickets and or osteomalacia of varying severity beginning in the first months of life and most of the individuals presents little or any body hair (alopecia). The main objective of this project was the molecular analysis of the vitamin D receptor (VDR) in four patients with vitamin D-dependent rickets type II that manifested with rickets and alopecia. DNA samples of these patients were used to sequence the VDR gene. The generated chromatograms were analyzed in specific programs, aiming the search of mutations. The analysis showed two novel missense mutation that result in amino acid change (Q259E e G319V) and one nonsense mutations (R73X). Fibroblast primary culture derived from the patients' skin biopsy was carried out for functional analysis of the receptor. Nuclear protein extract showed reduction of expression of all mutant receptors. The truncated VDR receptor containing only part of the DNA binding domain lost the region containing the epitopo which the antibody was raised against and it was not identified by the Western blot analysis. Treatment of the fibroblast primary culture treatment with increasing doses of l,25(OH)2 vitamin D showed that the mutant VDR were unable to be activated and to increase the expression of the 24-hydroxylase. It was found mutations in the four patients with vitamin D-dependent rickets type II studied. Functional analysis confirmed that the mutations impaired the VDR activation / Mestrado / Mestre em Farmacologia