RESUMO
OBJECTIVE: To determine whether multiple daily injections of parathyroid hormone (PTH) 1-34 are safe and effective as long-term therapy for children with hypoparathyroidism. STUDY DESIGN: Linear growth, bone accrual, renal function, and mineral homeostasis were studied in a long-term observational study of PTH 1-34 injection therapy in 14 children. METHODS: Subjects were 14 children with hypoparathyroidism attributable to autoimmune polyglandular syndrome type 1 (N = 5, ages 7-12 years) or calcium receptor mutation (N = 9, ages 7-16 years). Mean daily PTH 1-34 dose was 0.75 ± 0.15 µg/kg/day. Treatment duration was 6.9 ± 3.1 years (range 1.5-10 years). Patients were evaluated semiannually at the National Institutes of Health Clinical Center. RESULTS: Mean height velocity and lumbar spine, whole body, and femoral neck bone accretion velocities were normal throughout the study. In the first 2 years, distal one-third radius bone accrual velocity was reduced compared with normal children (P < .003). Serum alkaline phosphatase correlated with PTH 1-34 dose (P < .006) and remained normal (235.3 ± 104.8 [SD] U/L, N: 51-332 U/L). Mean serum and 24-hour urine calcium levels were 2.05 ± 0.11 mmol/L (N: 2.05-2.5 mmol/L) and 6.93 ± 1.3 mmol/24 hour (N: 1.25-7.5 mmol/24 hour), respectively-with fewer high urine calcium levels vs baseline during calcitriol and calcium treatment (P < .001). Nephrocalcinosis progressed in 5 of 12 subjects who had repeated renal imaging although renal function remained normal. CONCLUSIONS: Twice-daily or thrice-daily subcutaneous PTH 1-34 injections provided safe and effective replacement therapy for up to 10 years in children with hypoparathyroidism because of autoimmune polyglandular syndrome type 1 or calcium receptor mutation.
Assuntos
Estatura/efeitos dos fármacos , Hipoparatireoidismo/tratamento farmacológico , Hormônio Paratireóideo/uso terapêutico , Adolescente , Calcinose , Cálcio/sangue , Cálcio/urina , Criança , Creatinina/urina , Análise Mutacional de DNA , Feminino , Homeostase , Terapia de Reposição Hormonal , Humanos , Testes de Função Renal , Modelos Lineares , Masculino , Nefrocalcinose/metabolismo , Hormônio Paratireóideo/administração & dosagem , Fósforo/sangue , Fósforo/urina , Poliendocrinopatias Autoimunes/genética , Receptores de Detecção de Cálcio/genética , Resultado do Tratamento , Vitamina D/sangueRESUMO
OBJECTIVE: To compare the response with synthetic human parathyroid hormone (PTH) 1-34 delivered by twice-daily injection vs insulin pump in children with severe congenital hypoparathyroidism due to calcium receptor mutation or autoimmune polyglandular syndrome type 1. STUDY DESIGN: Children and young adults aged 7-20 years with congenital hypoparathyroidism (N = 12) were randomized to receive PTH 1-34, delivered either by twice-daily subcutaneous injection or insulin pump for 13 weeks, followed by crossover to the opposite delivery method. The principal outcome measures were serum and urine calcium levels. Secondary outcomes included serum and urine magnesium and phosphate levels and bone turnover markers. RESULTS: PTH 1-34 delivered via pump produced near normalization of mean serum calcium (2.02 ± 0.05 [pump] vs 1.88 ± 0.03 [injection] mmol/L, P < .05, normal 2.05-2.5 mmol/L), normalized mean urine calcium excretion (5.17 ± 1.10 [pump] vs 6.67 ± 0.76 mmol/24 h/1.73 m(2), P = .3), and significantly reduced markers of bone turnover (P < .02). Serum and urine calcium and magnesium showed a biphasic pattern during twice-daily injection vs minimal fluctuation during pump delivery. The PTH 1-34 dosage was markedly reduced during pump delivery (0.32 ± 0.04 vs 0.85 ± 0.11 µg/kg/d, P < .001), and magnesium supplements were also reduced (P < .001). CONCLUSION: Compared with twice-daily delivery, pump delivery of PTH 1-34 provides more physiologic calcium homeostasis and bone turnover in children with severe congenital hypoparathyroidism.
Assuntos
Hipoparatireoidismo/congênito , Hipoparatireoidismo/tratamento farmacológico , Hormônio Paratireóideo/administração & dosagem , Adolescente , Criança , Feminino , Humanos , Bombas de Infusão , Injeções Subcutâneas , Masculino , Índice de Gravidade de Doença , Adulto JovemRESUMO
Human mismatch repair (MMR) genes encode highly conserved interacting proteins that correct replication errors predisposing to hereditary gastrointestinal and genitourinary malignancies. We previously investigated expression of the prototype MMR gene hMSH2 in normal, benign prostatic hyperplasia and malignant prostate tissues (Velasco et al., Cancer 94:690-699, 2002). An association was detected between reduced hMSH2 staining and favorable outcome as determined by undetectable serum prostate specific antigen (PSA) after radical prostatectomy. We now investigate the association between clinicopathological variables and hMSH2 expression or microsatellite instability (MSI). A statistically significant association was found between tumors exhibiting MSI (MSI+ tumors) and lower preoperative serum PSA values, smaller tumor volumes and lower frequency of surgical specimens with extracapsular extension of tumor. No statistically significant association (P value less than or equal to 0.05) was found between hMSH2 staining and these clinicopathologic variables. Based on our analysis, we conclude that MMR deficiency has important clinicopathologic implications in prostate cancer. Furthermore, specific MMR genes may have different effects on prostate cancer biology.