RESUMO
INTRODUCTION: We describe ethical/moral issues in patient selection in a new living donor kidney transplant program in Guyana, South America. CASE REPORTS: Over 3 years, we screened 450 patients with chronic kidney disease among which 70 were suitable for kidney transplantation. There were five patients whose evaluations raised possible ethical dilemmas: one had nonadherence to dialysis; two of Guyanese origin living abroad wished to have the transplant performed in Guyana; a minor wished to donate to her mother; and another subject was considering commercialization of the transplant process. RESULTS: Since inception of the renal replacement program in 2008, we have completed 13 living kidney transplantations, 17 peritoneal dialysis placements, and 20 vascular access procedures. In the five patients wherein faced ethical dilemmas, three were rejected for consideration despite having living donors: one was nonadherent, the second excluded due to an attempt to commercialize the process, and the third, a minor who wished to donate to the mother. The other two patients were considered Guyanese ex-patriots acceptable for the program. DISCUSSION: The consequence of kidney failure in Guyana prior to introduction of renal replacement therapy was a virtual death sentence. These cases illustrate ethical dilemmas serving to throw into stark relief the implications of decisions made in a developing country versus those in a developing country.
Assuntos
Ética Médica , Transplante de Rim/ética , Transplante de Rim/métodos , Seleção de Pacientes/ética , Obtenção de Tecidos e Órgãos/ética , Adolescente , Adulto , Tomada de Decisões , Feminino , Guiana , Humanos , Falência Renal Crônica/cirurgia , Masculino , Cooperação do Paciente , Diálise Renal/métodosRESUMO
Nephrogenic diabetes insipidus (NDI) is an inherited disorder characterized by renal resistance to the antidiuretic effect of arginine vasopressin (AVP), resulting in polyuria, polydipsia, and hypoosmolar urine. In the vast majority of cases, NDI is associated with germ-line mutations in the vasopressin receptor type 2 gene (AVPR2) and in about 8% of the cases with the water channel aquaporin-2 gene (AQP-2) mutations. To date, approximately 277 families with 185 germ-line mutations in the AVPR2 gene have been described worldwide. In the present study, the AVPR2 gene was genotyped in eight unrelated Brazilian kindred with NDI. In five of these NDI families, novel mutations were noted (S54R, I130L, S187R, 219delT, and R230P), whereas three seemingly unrelated probands were found to harbor previously described AVPR2 gene mutations (R106C, R137H, R337X). Additionally a novel polymorphism (V281V) was detected. In conclusion, although NDI is a rare disease, the findings of mutations scattered over the entire coding region of the AVPR2 gene are a valuable model to determine structure function relationship in G-protein-coupled receptor related diseases. Furthermore, our data indicate that in Brazil the spectrum of AVPR2 gene mutations is "family specific".
Assuntos
Arginina Vasopressina/metabolismo , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/metabolismo , Mutação , Receptores de Vasopressinas/genética , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Brasil , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Fases de Leitura Aberta/genética , Linhagem , Receptores de Vasopressinas/classificação , Receptores de Vasopressinas/fisiologiaRESUMO
Haim-Munk syndrome (HMS) is a rare autosomal recessive disorder characterized clinically by abnormal palmoplantar hyperkeratosis and destruction of the periodontium, with hallmarks of onychogryphosis and arachnodactyly. Germline mutations in the lysosomal protease cathepsin C gene (CTSC) have been described in a single patient with HMS and in several individuals with the clinically related disorder Papillon-Lefevre syndrome (PLS). We describe a patient with HMS. We have analysed the cathepsin C gene in the proband and her mother. Sequence analysis of CTSC in the proband revealed a homozygous mutation at codon 196 (587T-->C) within exon 4 that altered the conserved leucine to proline (Leu196Pro), whereas the patient's mother was heterozygous for that mutation. The same mutation has previously been described in an unrelated Brazilian family with PLS. An identical single missense mutation in the cathepsin C gene may underlie both PLS and HMS. These findings confirm that HMS and PLS are allelic variants of cathepsin C gene mutations and suggest that other factors (environmental or genetic) may be important determinants of the clinical phenotype of HMS and PLS.
Assuntos
Catepsina C/genética , Ceratodermia Palmar e Plantar/genética , Mutação , Adulto , Feminino , Homozigoto , Humanos , Ceratodermia Palmar e Plantar/patologia , Doença de Papillon-Lefevre/genética , Linhagem , Análise de Sequência de DNA , SíndromeRESUMO
Craniopharyngioma is the most common childhood tumor and thought to arise from embryonic remnants of Rathke's pouch. The paucity of published data on the molecular basis of these tumors prompted us to examine 22 adamantinomatous craniopharyngiomas looking for genetic abnormalities. Using the X-linked polymorphic androgen receptor gene as a tool for X-chromosome inactivating analysis, we found that a subset of craniopharyngiomas are monoclonal and therefore are probably due to acquired somatic genetic defects. Thus, we investigated these tumours for mutations within three candidate genes, Gsalpha, Gi2alpha and patched (PTCH). Using single stranded conformational polymorphism (SSCP), denaturing gradient gel electrophoresis and direct sequencing, the presence of somatic mutations in these genes could not be demonstrated in any tumor. Our data indicate that a subset of craniopharyngiomas are monoclonal and the mutations in the PTCH, Gsalpha, and Gi2alpha contribute little if any to craniopharyngioma development.
Assuntos
Adenoma/genética , Neoplasias Encefálicas/genética , Craniofaringioma/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Proteínas Proto-Oncogênicas/genética , Adenoma/patologia , Anticorpos Monoclonais , Neoplasias Encefálicas/patologia , Craniofaringioma/patologia , Primers do DNA , Éxons/genética , Subunidade alfa Gi2 de Proteína de Ligação ao GTP , Humanos , Mutação/genética , Polimorfismo Conformacional de Fita Simples , Desnaturação Proteica , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The effect of dopamine over pulmonary edema induced by PAF was studied. Thirty preparations of rabbit lungs were used: six control preparations (CP), six PAF preparations (PP) in which we injected a dose of 1 microg/kg of rabbit weight and eighteen dopamine preparations (DAP) divided in three groups of six pretreated with a dose of 1-5 (dopaminergic range), 10-20 (Beta range) and 20-30 ug/kg/min (Alpha range) of dopamine, respectively for 30 min, followed by an injection of PAF as in the PP. DAP at Beta and Alpha-adrenergic range decreased pulmonary artery pressure (Pap) as compared to CP, with values of 11.66 (CI 95%: 10.83-12.48), 11.66 (CI 95%: 9.87-13.44) versus 17.12 (CI 95%: 16.12-18.11) cm of water, respectively. DAP in Beta and Alpha-adrenergic range prevented Pap increment as compared to PP, with values of 17.16 (CI 95%: 16.37-17.94), 17.5 (CI 95%: 14.93-20.06) versus 84 cm of water (CI 95%: 71.41-96.58), respectively. Dopamine, at its three ranges inhibited the augmentation of the fluid filtration rate observed in PP with values of 1.01 (CI 95%: 0.77-1.24), 0.03 (CI 95%: 0.01-0.04) and 0.02 g/min (CI 95%: -0.0004-0.03) versus 2.13 g/min (CI 95%: 1.56-2.69), respectively. We concluded that dopamine has a vasodilator effect on Pap and exerts an inhibiting action over PAF effects in pulmonary circulation. Such effects seem to be mainly mediated by Beta-receptors, rather than by dopaminergic receptors.
Assuntos
Dopamina/farmacologia , Fator de Ativação de Plaquetas/farmacologia , Edema Pulmonar/induzido quimicamente , Animais , Pressão Sanguínea/efeitos dos fármacos , Dopamina/administração & dosagem , Técnicas In Vitro , Mediadores da Inflamação/farmacologia , Perfusão , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar/efeitos dos fármacos , Edema Pulmonar/fisiopatologia , Coelhos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/fisiologia , Vasodilatação/efeitos dos fármacosRESUMO
Parathyroid adenomas are usually benign uniglandular tumors, and inactivation of several tumor suppressor genes, notably the MEN 1 gene, or activation of oncogenes have been implicated in the tumorigenesis. Genomic instability, indicative of the involvement of DNA mismatch repair genes, has not been previously described in parathyroid adenomas. A single large parathyroid adenoma was resected from an 8.5-yr-old Brazilian patient with no personal or family history of other endocrinopathies. Analysis of paired tumor-nontumor DNA using 23 microsatellite markers, located on chromosomes 1, 10, and 11 was carried out. Microsatellite instability was detected in nine markers (D1S191, D1S212, D1S413, D1S2848, RET, D11S901, D11S903, INSR, and INT2), whereas no allelic loss was detected with any of the analyzed markers. Immunohistochemical analysis of retinoblastoma protein expression revealed low levels of expression, but no histopathological signs of malignancy. We conclude that in this single, apparently sporadic parathyroid adenoma, DNA mismatch repair genes might be involved in parathyroid tumorigenesis.
Assuntos
Adenoma/genética , Repetições de Microssatélites/genética , Neoplasias das Paratireoides/genética , Adenoma/complicações , Criança , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Feminino , Humanos , Hiperparatireoidismo/etiologia , Imuno-Histoquímica , Neoplasias das Paratireoides/induzido quimicamente , Reação em Cadeia da PolimeraseRESUMO
Nephrogenic diabetes insipidus (NDI) is associated with germline mutations in two genes: vasopressin receptor type 2 (V2(R)) in X-linked NDI, and the water channel aquaporin-2, in autosomal-recessive disease. Genetic heterogeneity is further emphasized by reports of phenotypically abnormal individuals with normal structural genes. We analyzed both genes in five Brazilian families and the aquaporin-2 gene in two Swedish families with clinical and laboratory diagnosis of NDI, by a combination of denaturing gradient gel electrophoresis (DGGE) and direct DNA sequencing. A novel polymorphism in the aquaporin-2 gene (S167S), but no disease-associated mutations in any tested individual from all seven families, was detected. In two Brazilian families, frameshift mutations were detected in the V2(R) gene: one leading to a premature stop after codon 36 and the other to a longer peptide (462 aa instead of the 373 aa wild-type protein). In two other Brazilian families, probable disease-associated missense mutations were detected: an alanine to proline at codon 163 (A163P) and an asparagine to aspartic acid at codon 85 (D85N). In one Brazilian family, both genes were structurally normal and the aquaporin-2 gene was also normal in the two Swedish kindreds. This report further extends the mutational spectrum of NDI and suggests that there are other mutational or epigenetic events inactivating the two known genes or even novel genes that underlie NDI.
Assuntos
Aquaporinas/genética , Diabetes Insípido Nefrogênico/genética , Receptores de Vasopressinas/genética , Adolescente , Adulto , Aquaporina 2 , Aquaporina 6 , Arginina Vasopressina/sangue , Brasil , Criança , Análise Mutacional de DNA , Diabetes Insípido Nefrogênico/sangue , Diabetes Insípido Nefrogênico/diagnóstico , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Lactente , Masculino , Mutação , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Análise de Sequência de DNA , SuéciaRESUMO
OBJECTIVES AND STUDY DESIGN: Squamous cell carcinomas are common malignancies and a major cause of mortality. The molecular mechanisms involved in tumorigenesis remain largely unknown, but sequence alterations have been identified in coding regions of several genes. Primary squamous cell carcinomas of various tissues (skin, head and neck, esophagus, lung, penis, uterus, and vagina) from 52 patients were analyzed for the presence of mutations within several candidate genes presumably involved in tumorigenesis: Gsalpha, Gi2alpha, GTPase activating protein (GAP), and patched (PTCH) genes. METHODS: Mutational analysis scheme included polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGGE), single stranded conformational polymorphism (SSCP), and selected sequence analysis. RESULTS AND CONCLUSION: No tumor had any evidence of mutations in any of these analyzed genes. Mutations within these genes do not occur frequently in an unselected population of patients with squamous cell carcinomas.
Assuntos
Carcinoma de Células Escamosas/genética , Mutação Puntual/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Éxons/genética , Feminino , Proteínas de Ligação ao GTP/genética , Humanos , Masculino , Reação em Cadeia da Polimerase/métodos , Polimorfismo Genético/genéticaRESUMO
BACKGROUND: Myxoma is a rare bone tumor of the mandible and maxillary sinus whose etiology and underlying molecular mechanisms remain unknown. Mutations that inhibit the GTPase activity of the a subunit of the stimulating G protein (Gsa) have been demonstrated in the myocardium of patients with McCune-Albright syndrome. The histopathological similarities shared by cardiac and jaw myxomas coupled with the paucity of reported candidate genes involved in jaw tumor pathogenesis, prompted us to investigate for the presence of gsp mutations in 23 sporadic jaw myxomas. MATERIALS AND METHODS: We used the polymerase chain reaction (PCR) to amplify the appropriate genomic fragments, followed by denaturing gradient gel electrophoresis (DGGE) analysis. RESULTS: No gsp mutations could be demonstrated in any of tumors analyzed, while the technique has a proven capability to detect these specific mutations. CONCLUSIONS: We conclude that mutations of the Gs alpha gene rarely, if ever, are associated with sporadic jaw myxomas tumorigenesis.