RESUMEN
There is limited understanding of how asfotase alfa affects mineral metabolism and bone turnover in adults with pediatric-onset hypophosphatasia. This study showed that adults with hypophosphatasia treated with asfotase alfa experienced significant changes in biochemical markers of bone and mineral metabolism, possibly reflecting enhanced bone remodeling of previously osteomalacic bone. INTRODUCTION: Hypophosphatasia (HPP), due to a tissue nonspecific alkaline phosphatase (TNSALP) deficiency, can cause impaired bone mineralization and turnover. Although HPP may be treated with asfotase alfa, an enzyme replacement therapy, limited data are available on how treatment with asfotase alfa affects mineral metabolism and bone turnover in adults with HPP. METHODS: ALP substrates, bone turnover and mineral metabolism markers, and bone mineral density (BMD) data from EmPATHY, a single-center, observational study of adults (≥ 18 years) with pediatric-onset HPP treated with asfotase alfa (NCT03418389), were collected during routine clinical care and analyzed from baseline through 24 months of treatment. RESULTS: Data from 21 patients showed significantly increased ALP activity and reduced urine phosphoethanolamine (PEA)/creatinine (Cr) ratios after baseline through 24 months of asfotase alfa treatment. There were significant transient increases in parathyroid hormone 1-84 (PTH), osteocalcin, and procollagen type 1 N-propeptide (P1NP) levels at 3 and 6 months and in tartrate-resistant acid phosphatase 5b (TRAP5b) levels at 3 months, with a significant decrease in N-terminal telopeptide of type 1 collagen (NTX) levels at 24 months. Lumbar spine BMD T scores continuously increased during treatment. CONCLUSION: Significant changes in bone turnover and mineral metabolism markers after asfotase alfa treatment suggest that treatment-mediated mineralization may enable remodeling and bone turnover on previously unmineralized surfaces. Urine PEA/Cr ratios may be a useful parameter in monitoring treatment during routine care.
Asunto(s)
Fosfatasa Alcalina , Hipofosfatasia , Adulto , Remodelación Ósea , Niño , Humanos , Hipofosfatasia/tratamiento farmacológico , Inmunoglobulina G , Minerales , Proteínas Recombinantes de FusiónRESUMEN
Iron is a necessary substrate for neuronal function throughout the lifespan, but particularly during development. Early life iron deficiency (ID) in humans (late gestation through 2-3 yr) results in persistent cognitive and behavioral abnormalities despite iron repletion. Animal models of early life ID generated using maternal dietary iron restriction also demonstrate persistent learning and memory deficits, suggesting a critical requirement for iron during hippocampal development. Precise definition of the temporal window for this requirement has been elusive due to anemia and total body and brain ID inherent to previous dietary restriction models. To circumvent these confounds, we developed transgenic mice that express tetracycline transactivator regulated, dominant negative transferrin receptor (DNTfR1) in hippocampal neurons, disrupting TfR1 mediated iron uptake specifically in CA1 pyramidal neurons. Normal iron status was restored by doxycycline administration. We manipulated the duration of ID using this inducible model to examine long-term effects of early ID on Morris water maze learning, CA1 apical dendrite structure, and defining factors of critical periods including parvalbmin (PV) expression, perineuronal nets (PNN), and brain-derived neurotrophic factor (BDNF) expression. Ongoing ID impaired spatial memory and resulted in disorganized apical dendrite structure accompanied by altered PV and PNN expression and reduced BDNF levels. Iron repletion at P21, near the end of hippocampal dendritogenesis, restored spatial memory, dendrite structure, and critical period markers in adult mice. However, mice that remained hippocampally iron deficient until P42 continued to have spatial memory deficits, impaired CA1 apical dendrite structure, and persistent alterations in PV and PNN expression and reduced BDNF despite iron repletion. Together, these findings demonstrate that hippocampal iron availability is necessary between P21 and P42 for development of normal spatial learning and memory, and that these effects may reflect disruption of critical period closure by early life ID.
Asunto(s)
Hipocampo/crecimiento & desarrollo , Deficiencias de Hierro , Memoria/fisiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptores de Transferrina/metabolismo , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/embriología , Región CA1 Hipocampal/metabolismo , Región CA3 Hipocampal/citología , Región CA3 Hipocampal/embriología , Región CA3 Hipocampal/metabolismo , Células CHO , Cricetinae , Dendritas/metabolismo , Matriz Extracelular/metabolismo , Femenino , Hipocampo/citología , Hipocampo/embriología , Humanos , Interneuronas/metabolismo , Hierro/farmacología , Hierro de la Dieta/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/metabolismo , Parvalbúminas/metabolismo , Embarazo , Células Piramidales/embriología , Células Piramidales/metabolismo , Receptores de Transferrina/genética , Factores de TiempoRESUMEN
Bone loss has been observed within the first six months after HCT in both children and adults. While there is some evidence that bone formation may be reduced in children after HCT, it is currently unknown whether bone resorption is increased. The objective of this prospective study was to evaluate changes in markers of bone resorption over the first six months after pediatric HCT. Twenty-six participants (eight females) aged 10.9 ± 3.4 yr entered the study prior to HCT. Bone resorption was measured by urine DPD and PYD, and by plasma NTX and CTX. Seventeen participants who completed day +30 visit and either day +100 or +180 visits were included in the analysis. DPD increased between days +30 and +100 (mean change, 11.3 nmol/nmol creatinine; p = 0.012) and between days +30 and +180 (13.7 nmol/nmol creatinine; p = 0.036). PYD increased between days +30 and +100 (32 nmBCE/L; p = 0.019). CTX increased between baseline and day +100 (5.9 µg/L; p = 0.012). Changes in NTX levels were not statistically significant. This study shows that markers of bone resorption increase in children after HCT, suggesting that increased resorption may be a contributing factor to the pathophysiology of bone loss after pediatric HCT.
Asunto(s)
Biomarcadores/metabolismo , Resorción Ósea , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Anemia Aplásica/terapia , Densidad Ósea , Niño , Anemia de Fanconi/terapia , Femenino , Homeostasis , Humanos , Leucemia/terapia , Linfoma/terapia , Masculino , Osteoporosis/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Robinow syndrome (RS) is a rare genetic condition with two inheritance forms, autosomal dominant RS (DRS) and autosomal recessive RS (RRS). The characteristic features of this syndrome overlap in both inheritance forms, which make the clinical differential diagnosis difficult, especially in isolated cases. The objective of this study was to identify differences in the craniofacial and intraoral phenotype of patients with DRS and RRS. The characteristics and frequency of 13 facial and 13 intraoral clinical features associated with both DRS and RRS were assessed by direct dysmorphology examination and using a digital photographic analysis in 12 affected subjects. Although the phenotypic presentation varied and overlapped in the two forms of the syndrome, there were differences in the severity of the craniofacial and intraoral features. The craniofacial dysmorphology of RS was more severe in RRS. Nasal anomalies were the most frequent craniofacial features in both DRS and RRS. In contrast, intraoral features such as wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding and hypodontia were more severe in patients with DRS. Overall, facial characteristics appeared less pronounced in adult subjects compared to younger subjects. Craniofacial and intraoral findings are highly variable in RS, with abnormalities of the intraoral structures being more prominent in the DRS form. We propose that the difference in the alveolar ridge deformation pattern and severity of other intraoral characteristics could enhance the differential diagnosis of the two forms of this syndrome.
Asunto(s)
Deformidades Congénitas de las Extremidades/patología , Anomalías Maxilofaciales/patología , Anomalías de la Boca/patología , Cráneo/anomalías , Adolescente , Adulto , Anciano , Niño , Enanismo/genética , Enanismo/patología , Femenino , Humanos , Deformidades Congénitas de las Extremidades/genética , Masculino , Anomalías Maxilofaciales/genética , Persona de Mediana Edad , Anomalías de la Boca/genética , Fenotipo , Columna Vertebral/anomalías , Columna Vertebral/patologíaRESUMEN
Short stature is characteristic of Hurler syndrome, or mucopolysaccharidosis type IH (MPS IH). Hematopoietic stem cell transplantation (HSCT) is used to treat children with MPS IH. While HSCT corrects some of the metabolic features of MPS IH, its effects on growth are not well delineated. We investigated growth in patients with MPS IH after HSCT and described accompanying endocrine abnormalities. A cohort of 48 patients with MPS IH who had received HSCT between 1983 and 2005 were included. The prevalence of short stature (height <-2 s.d. score, SDS) before HSCT was 9%, and increased to 71% at last follow-up (6.9+/-5.1 years after HSCT). Short stature was positively associated with increased age at HSCT (P=0.002) and TBI (P=0.009). In total, 23% had growth hormone deficiency and/or low insulin-like growth factor-1, one female patient had premature adrenarche, one precocious puberty and 27% had clinical or subclinical hypothyroidism. Growth failure is highly prevalent in children with MPS IH after HSCT. Children who had no TBI exposure and were younger at the time of HSCT had a better height outcome.
Asunto(s)
Desarrollo del Adolescente/efectos de la radiación , Desarrollo Infantil/efectos de la radiación , Trasplante de Células Madre Hematopoyéticas , Mucopolisacaridosis I/terapia , Acondicionamiento Pretrasplante/efectos adversos , Irradiación Corporal Total/efectos adversos , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodosRESUMEN
To explore potential roles for lactogenic hormones in human fetal development, we examined the distribution and ontogenesis of expression of prolactin receptors (PRLRs) in human fetal tissues at 7.5-14 wk of gestation and in tissues of the embryonic and fetal rat on days e12.5-e20.5. Histochemical analysis of PRLR immunoreactivity in the human fetus and fetal rat revealed novel and unexpected patterns of receptor expression. Most remarkable was the appearance in early fetal development of intense PRLR immunoreactivity in tissues derived from embryonic mesoderm, including the periadrenal and perinephric mesenchyme, the pulmonary and duodenal mesenchyme, the cardiac and skeletal myocytes, and the mesenchymal precartilage and maturing chondrocytes of the endochondral craniofacial and long bones, vertebrae and ribs. Striking changes in the cellular distribution and magnitude of expression of PRLRs were noted in many tissues during development. In the fetal adrenal the initial mesenchymal PRLR expression is succeeded by the emergence of PRLR immunoreactivity in deeper fetal cortical cell layers. In the fetal kidney and lung, the invagination of cortical mesenchyme is accompanied by progressive PRLR immunoreactivity in bronchial and renal tubular epithelial cells. In the pancreas, the PRLR is expressed primarily in acinar cells and ducts in early gestation; in late gestation and in the postnatal period, the PRLR is expressed predominantly in pancreatic islets, co-localizing with insulin and glucagon. Finally in fetal hepatocytes, PRLR immunoreactivity increases significantly between embryonic days e52 and e96 in the human fetus and between days e16.5 and e18.5 in the fetal rat. In addition to playing important roles in reproduction, lactation, and immune function, the lactogenic hormones likely play roles in tissue differentiation and organ development early in gestation.
Asunto(s)
Embrión de Mamíferos/metabolismo , Desarrollo Embrionario y Fetal , Feto/metabolismo , Receptores de Prolactina/metabolismo , Glándulas Suprarrenales/crecimiento & desarrollo , Glándulas Suprarrenales/metabolismo , Animales , Desarrollo Óseo , Huesos/metabolismo , Cartílago/crecimiento & desarrollo , Cartílago/metabolismo , Clonación Molecular , Sondas de ADN/genética , Duodeno/crecimiento & desarrollo , Duodeno/metabolismo , Electroforesis en Gel de Agar , Regulación del Desarrollo de la Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/inmunología , Corazón/crecimiento & desarrollo , Humanos , Inmunohistoquímica , Riñón/crecimiento & desarrollo , Riñón/metabolismo , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Pulmón/crecimiento & desarrollo , Pulmón/metabolismo , Mesodermo/metabolismo , Miocardio/metabolismo , Páncreas/crecimiento & desarrollo , Páncreas/metabolismo , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Ratas , Receptores de Prolactina/genética , Receptores de Prolactina/inmunologíaRESUMEN
Gonadal failure is a health and quality-of-life concern in hematopoietic cell transplant (HCT) survivors. While ovarian dysfunction is nearly universal following myeloablative (MA) conditioning, the risk is unclear after reduced-intensity conditioning (RIC). Gonadotropin-releasing hormone agonists decrease ovarian failure rates following conventional chemotherapy, but little is known about its effectiveness with HCT. We investigated the impact of leuprolide on ovarian function after MA conditioning and monitored ovarian function after RIC in this descriptive pilot study. Post-menarchal females <50 years undergoing HCT with adequate baseline ovarian function (follicle-stimulating hormone (FSH) level <40 mIU/mL and normal menstruation) were eligible. Prior to MA conditioning, leuprolide was administered. Those undergoing RIC were observed. FSH was measured at various time points. Seventeen women aged 12-45 years were evaluated (7 in the intervention group and 10 in the observation group). Compared to the historical high rate of ovarian failure after MA conditioning, 3 of 7 evaluable Lupron recipients had ovarian failure at a median of 703 days post transplant. Ovarian failure occurred in 1 of 10 recipients of RIC at a median follow-up of 901 days. In conclusion, leuprolide may protect ovarian function after MA conditioning. Additionally, RIC with cyclophosphamide, fludarabine and low-dose TBI has a low risk of ovarian failure.
Asunto(s)
Hormona Liberadora de Gonadotropina/agonistas , Trasplante de Células Madre Hematopoyéticas/métodos , Leuprolida/uso terapéutico , Ovario/efectos de los fármacos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Niño , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Persona de Mediana Edad , Agonistas Mieloablativos , Pruebas de Función Ovárica , Ovario/fisiología , Proyectos Piloto , Adulto JovenRESUMEN
Previous studies have shown that lactogenic hormones stimulate beta-cell proliferation and insulin production in pancreatic islets. However, all such studies have been conducted in cells incubated in medium containing glucose. Since glucose independently stimulates beta-cell replication and insulin production, it is unclear whether the effects of prolactin (PRL) on insulin gene expression are exerted directly or through the uptake and/or metabolism of glucose. We examined the interactions between glucose and PRL in the regulation of insulin gene transcription and the expression of glucose transporter-2 (glut-2) and glucokinase mRNAs in rat insulinoma (INS-1) cells. In the presence of 5.5 mM glucose, the levels of preproinsulin and glut-2 mRNAs in PRL-treated cells exceeded the levels in control cells (1.7-fold, P<0.05 and 2-fold, P<0.05 respectively). The maximal effects of PRL were noted at 24-48 h of incubation. PRL had no effect on the levels of glucokinase mRNA. The higher levels of glut-2 mRNA were accompanied by an increase in the number of cellular glucose transporters, as demonstrated by a 1. 4- to 2.4-fold increase in the uptake of 2-deoxy-d-[(3)H]glucose in PRL-treated INS-1 cells (P<0.001). These findings suggested that the insulinotropic effect of PRL is mediated, in part, by induction of glucose transport and/or glucose metabolism. Nevertheless, even in the absence of glucose, PRL stimulated increases in the levels of preproinsulin mRNA (3.4-fold higher than controls, P<0.0001) and glut-2 mRNA (2-fold higher than controls, P<0.01). These observations suggested that PRL exerts glucose-independent as well as glucose-dependent effects on insulin gene expression. Support for this hypothesis was provided by studies of insulin gene transcription using INS-1 cells transfected with a plasmid containing the rat insulin 1 promoter linked to a luciferase reporter gene. Glucose and PRL, alone and in combination, stimulated increases in cellular luciferase activity. The relative potencies of glucose (5.5 mM) alone, PRL alone, and glucose plus PRL in combination were 2.2 (P<0.001), 3.4 (P<0.01), and 7.9 (P<0.0001) respectively. Our findings suggest that glucose and PRL act synergistically to induce insulin gene transcription.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Insulina/genética , Insulinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Prolactina/farmacología , Animales , Northern Blotting , Medios de Cultivo , Citocalasina B/farmacología , Sinergismo Farmacológico , Glucoquinasa/genética , Glucosa/metabolismo , Transportador de Glucosa de Tipo 2 , Luciferasas/genética , Proteínas de Transporte de Monosacáridos/genética , Proinsulina/genética , Precursores de Proteínas/genética , ARN Mensajero/análisis , Ratas , Células Tumorales CultivadasRESUMEN
We describe 19 males with Aarskog syndrome who were treated with growth hormone (GH) and enrolled in the National Cooperative Growth Study (NCGS). There was a significant increase in both growth rate (3.9 +/- 1.9 cm/yr vs 8.9 +/- 1.7 cm/yr, p < 0.001) and height SD score (change in HtSDS = 1.0 +/- 0.8). The increase in HtSDS was dependent on treatment duration, frequency of injections, weight-for-height SDS, and HtSDS at enrollment. The results of our study suggest a positive effect of GH treatment on growth and adult height in Aarskog syndrome patients.
Asunto(s)
Estatura/efectos de los fármacos , Enanismo/terapia , Hormona del Crecimiento/uso terapéutico , Adolescente , Determinación de la Edad por el Esqueleto , Niño , Anomalías Craneofaciales/diagnóstico , Relación Dosis-Respuesta a Droga , Enanismo/diagnóstico , Genitales Masculinos/anomalías , Crecimiento/efectos de los fármacos , Hormona del Crecimiento/administración & dosificación , Humanos , Masculino , Síndrome , TiempoRESUMEN
Low bone mineral density (BMD) has been reported in recipients of pediatric hematopoietic cell transplantation (HCT), but it is unclear whether age at HCT has a role. The objective of this cross-sectional study was to determine if patients treated with HCT before the age of 10 years have long-term BMD deficits compared with patients transplanted at an older age and with sibling controls. The study included 151 HCT recipients (87 males), age at study 24.7±8.6 years treated with HCT for hematologic malignancies at age 10.9±6.4 years, and 92 healthy sibling controls (49 males), age at study 22.3±8.0 years. Dual-energy x-ray absorptiometry was performed to measure BMD Z-scores for total body BMD (TBMD), lumbar spine BMD (LBMD) and femoral neck BMD (FNBMD, for subjects î¶20 years at study visit). Patients <10 years at HCT had significantly lower TBMD and FNBMD Z-scores (by 0.5 and 0.8 s.d., respectively) compared with controls (P=0.003 and P=0.0001, respectively) and patients >18 years at HCT (P=0.04 and P=0.004, respectively) at an average of 14 years after HCT. In conclusion, this study identified young age at transplant as an important risk factor for bone deficits in young adulthood, suggesting that efforts to reduce bone loss should focus on this patient population.
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Absorciometría de Fotón/métodos , Enfermedades Óseas Metabólicas/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Osteoporosis/etiología , Acondicionamiento Pretrasplante/efectos adversos , Adolescente , Adulto , Densidad Ósea , Enfermedades Óseas Metabólicas/diagnóstico por imagen , Niño , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Acondicionamiento Pretrasplante/métodos , Adulto JovenRESUMEN
Magnetic nanoparticles excited by alternating magnetic fields (AMF) have demonstrated effective tumor-specific hyperthermia. This treatment is effective as a monotherapy as well as a therapeutic adjuvant to chemotherapy and radiation. Iron oxide nanoparticles have been shown, so far, to be non-toxic, as are the exciting AMF fields when used at moderate levels. Although higher levels of AMF can be more effective, depending on the type of iron oxide nanoparticles use, these higher field strengths and/or frequencies can induce normal tissue heating and toxicity. Thus, the use of nanoparticles exhibiting significant heating at low AMF strengths and frequencies is desirable. Our preliminary experiments have shown that the aggregation of magnetic nanoparticles within tumor cells improves their heating effect and cytotoxicity per nanoparticle. We have used transmission electron microscopy to track the endocytosis of nanoparticles into tumor cells (both breast adenocarcinoma (MTG-B) and acute monocytic leukemia (THP-1) cells). Our preliminary results suggest that nanoparticles internalized into tumor cells demonstrate greater cytotoxicity when excited with AMF than an equivalent heat dose from excited external nanoparticles or cells exposed to a hot water bath. We have also demonstrated that this increase in SAR caused by aggregation improves the cytotoxicity of nanoparticle hyperthermia therapy in vitro.
RESUMEN
Twisted gastrulation (TWSG1), an extracellular regulator of bone morphogenetic protein (BMP) signaling, is critical for embryonic brain development. Mice deficient in TWSG1 have abnormal forebrain development manifesting as holoprosencephaly. The expression and potential roles of TWSG1 in postnatal brain development are less well understood. We show that Twsg1 is expressed in the adult mouse brain in the choroid plexus (CP), hippocampus, and other regions, with the strongest expression observed in CP. TWSG1 was also detected in a human fetal brain at mid-gestation, with highest levels in the epithelium of CP. Bmp1, Bmp2, Bmp4-Bmp7 as well as BmprIA and BmprII, but not BmprIB, were expressed in CP. BMP antagonists Chordin (Chrd) and Noggin were not detected in CP, however Chrd-like 1 and brain-specific Chrd-like (Brorin) were expressed. Electrophysiological study of synaptic plasticity revealed normal paired-pulse facilitation and long-term potentiation in the CA1 region of hippocampus in Twsg1(-/-) mice. Among the homozygous mutants that survive beyond the first 2 weeks, the prevalence of hydrocephalus was 4.3%, compared to 1.5% in a wild type colony (P=0.0133) between 3 and 10 weeks of life. We detected a high level of BMP signaling in CP in wild type adult mice that was 17-fold higher than in the hippocampus (P=0.005). In contrast, transforming growth factor beta (TGFbeta) signaling was predominant in the hippocampus. Both BMP signaling and the expression of BMP downstream targets Msx1 and Msx2 were reduced in CP in Twsg1(-/-) mice. In summary, we show that Twsg1 is expressed in the adult mouse and human fetal CP. We also show that BMP is a branch of TGFbeta superfamily that is dominant in CP. This presents an interesting avenue for future research in light of the novel roles of CP in neural progenitor differentiation and neuronal repair, especially since TWSG1 appears to be the main regulator of BMP present in CP.
Asunto(s)
Encéfalo/metabolismo , Proteínas/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Receptores de Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Plexo Coroideo/metabolismo , Potenciales Postsinápticos Excitadores , Hipocampo/embriología , Hipocampo/crecimiento & desarrollo , Hipocampo/fisiología , Humanos , Hidrocefalia/genética , Ligandos , Potenciación a Largo Plazo , Ratones , Ratones Noqueados , Mutación , Unión Proteica , Proteínas/genética , Transducción de Señal , Sinapsis/fisiología , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
Autosomal recessive osteopetrosis (OP) is characterized by insufficient osteoclast activity resulting in defective bone resorption and marked increase in skeletal mass and density. OP has been successfully treated with hematopoietic cell transplantation (HCT), secondary to engraftment of donor-derived functioning osteoclasts resulting in remodeling of bone and establishment of normal hematopoiesis. Although hypercalcemia is a common presenting feature of OP, it may be observed following HCT due to engraftment of osteoclasts differentiated from the hematopoietic precursors. To characterize hypercalcemia after HCT-who is at risk, onset, duration and response to treatment-we evaluated 15 patients with OP treated at the University of Minnesota from 2000 to 2009. Hypercalcemia, defined as any single calcium >11.0 mg/100 ml after the first transplant, was found in 40% of patients. Median onset of hypercalcemia was 23 days and the duration was 2-24 days. Hypercalcemia was more common in patients older than 2 years of age at the time of HCT. Treatment with hydration, furosemide and s.c. calcitonin resolved hypercalcemia and resulted in no severe adverse events. In conclusion, hypercalcemia is common in patients with OP within the first 4 weeks after HCT, and more likely in older patients. Isotonic saline, furosemide and s.c. calcitonin were well-tolerated and effective treatments in our study population.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hipercalcemia/complicaciones , Osteopetrosis/terapia , Adolescente , Adulto , Niño , Preescolar , Humanos , Hipercalcemia/terapia , Lactante , Adulto JovenAsunto(s)
Médula Ósea/enzimología , Médula Ósea/patología , Germinoma/patología , Células Madre Hematopoyéticas/enzimología , Células Madre Hematopoyéticas/patología , Telomerasa/metabolismo , Antígenos CD/análisis , Niño , Germinoma/enzimología , Humanos , Inmunofenotipificación , Reacción en Cadena de la PolimerasaRESUMEN
Wolman disease is the infantile form of autosomal recessive acid lipase deficiency, typically presenting in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands. Hematopoietic cell transplantation (HCT) is the only therapy reported to prevent hepatic failure and death, which without treatment occurs within the first year of life. We report a single institution's experience with HCT treatment of four Wolman patients, two of whom are long-term survivors (the longest survival reported to date, (4 and 11 years). Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function. The older patient has normal adaptive functions but mild to moderate neurocognitive deficiencies thought to be secondary to treatment and other medical problems. The younger patient has age-appropriate neurodevelopmental and adaptive abilities. We conclude that Wolman disease can be successfully treated with HCT, and that hepatic and cognitive function can be preserved with early diagnosis and timely referral to a transplant center.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedad de Wolman/terapia , Sistema Endocrino/patología , Femenino , Tracto Gastrointestinal/patología , Sistema Hematopoyético/patología , Humanos , Lactante , Recién Nacido , Hígado/patología , Masculino , Sobrevivientes , Enfermedad de Wolman/metabolismo , Enfermedad de Wolman/patología , Enfermedad de Wolman/psicologíaRESUMEN
Children with Hurler syndrome experience progressive growth failure after hematopoietic cell transplantation (HCT). The goal of this study was to review the safety and efficacy of growth hormone (GH) in eight children with Hurler syndrome who were treated at our institution with GH for short stature or GH deficiency between 2005 and 2008. The age at initiation of treatment with GH was 9.6+/-2.3 years and time since HCT was 7.5+/-1.5 years. Mean GH dose was 0.32 mg/kg/week. Baseline growth velocity was 3.5+/-1.5 cm/year (-2.6+/-1.9 s.d.), and it increased to 5.2+/-3.0 cm/year (-0.1+/-3.6 s.d.) after 1 year of treatment. Of the six patients with radiographic data, there was one progression of scoliosis, one progression of kyphosis and one progression of genu valgum. No patient discontinued treatment due to progression of skeletal disease. One patient discontinued GH due to slipped capital femoral epiphysis. Preliminary data suggest that 1-year GH treatment may modestly improve growth velocity in children with Hurler syndrome.
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Trasplante de Células Madre Hematopoyéticas , Hormona de Crecimiento Humana/uso terapéutico , Mucopolisacaridosis I/terapia , Adolescente , Niño , Estudios de Cohortes , Femenino , Hormona de Crecimiento Humana/efectos adversos , Hormona de Crecimiento Humana/deficiencia , Humanos , Masculino , Mucopolisacaridosis I/tratamiento farmacológico , Proteínas Recombinantes/farmacología , Estudios RetrospectivosAsunto(s)
Glándulas Suprarrenales/fisiopatología , Adrenoleucodistrofia/fisiopatología , Adrenoleucodistrofia/terapia , Trasplante de Células Madre Hematopoyéticas , Recuperación de la Función , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
Variations in ecdysteroid titers play crucial roles in arthropods by initiating and regulating molting and metamorphosis. The recent identification of genes coding for cytochrome P450 enzymes involved in Drosophila ecdysteroidogenesis provides new molecular tools to investigate the regulation of insect hormone production. In the present study, we used an enzyme immunoassay to show that the molting hormone titer is strictly correlated with the steroidogenic capacity of the ring gland. A temporal correlation between dynamics of ecdysone production and expression of genes encoding steroidogenic enzymes was observed during the third instar, suggesting that the timing of hormone production depends on transcriptional regulation of the biosynthetic enzymes. Using clonal analysis, levels of two steroidogenic enzymes, Phantom (PHM) and Disembodied (DIB), were shown to be very reduced in ftz transcription factor 1 (ftz-f1) mutant ring gland cells whereas there was no effect of the without children (woc) mutation, suggesting that FTZ-F1 regulates phm and dib expression. Since betaFTZ-F1 is the homolog of the vertebrate steroidogenic factor 1 (SF1), which plays a key role in the differentiation of vertebrate steroidogenic organs through transcriptional regulation of steroidogenic enzymes, this study emphasizes the strong parallels between insects and vertebrates with respect to the regulatory mechanisms of steroidogenesis.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Drosophila melanogaster/crecimiento & desarrollo , Ecdisteroides/biosíntesis , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Muda/fisiología , Factores de Transcripción/metabolismo , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Cartilla de ADN , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Ecdisteroides/genética , Técnicas para Inmunoenzimas , Hibridación in Situ , Proteínas de Insectos , Larva/crecimiento & desarrollo , Larva/metabolismo , Oxigenasas de Función Mixta/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
To explore the roles of lactogens in islet function, we generated a stable line of rat insulinoma (INS-1) cells that express rat placental lactogen II (rPLII) constitutively in culture. We used this cell line (Ins-rPLII) to examine the effects of endogenous rPLII on beta-cell growth, islet formation, and the expression of glucose transporter 2 (glut-2) and insulin mRNA. Growth and maturation of Ins-rPLII cells were compared with that of cells transfected stably with an empty expression plasmid (control) and of INS-1 cells treated with exogenous prolactin. The Ins-rPLII cells proliferated more rapidly than control cells in serumfree medium and showed distinct morphologic characteristics in culture. Whereas the control cells flattened readily on plastic and formed a branching monolayer, the Ins-rPLII cells remained more rounded, sent out fewer projections, and formed more numerous (p<0.01) and larger (p<0.01) beta-cell clusters. Larger clusters assumed a spherical form with well-delineated smooth borders and detached more readily from the culture plates. Maturational progression of the Ins-rPLII cells was associated with a 40% increase in preproinsulin mRNA (p<0.05) and a 2-3-fold increase in glut-2 mRNA (p<0.01). Induction of glut-2 mRNA was accompanied by a 1.4-2.4-fold increase (p< 0.01) in the uptake of radiolabeled 2-deoxyglucose. Similar effects were observed in INS-1 cells exposed for 48 h to exogenous prolactin. These findings suggest novel roles for the lactogenic hormones in the maturation and growth of pancreatic islets. Lactogen induction of beta-cell aggregation coupled with localized beta-cell growth may contribute to the expansion of islet mass that occurs in pregnancy and during the perinatal period. The induction of insulin and glut-2 mRNA provides a mechanism by which the lactogens may increase fetal and maternal insulin production and enhance the sensitivity of the pancreas to glucose.
Asunto(s)
Regulación de la Expresión Génica , Islotes Pancreáticos/metabolismo , Lactógeno Placentario/metabolismo , Animales , Northern Blotting , Western Blotting , División Celular , Línea Celular , Transportador de Glucosa de Tipo 2 , Inmunohistoquímica , Insulina/genética , Islotes Pancreáticos/citología , Islotes Pancreáticos/crecimiento & desarrollo , Linfoma/patología , Proteínas de Transporte de Monosacáridos/genética , ARN Mensajero/genética , Ratas , Células Tumorales CultivadasRESUMEN
The reciprocal influence of body postures on the oral structures, but also of the oral structures on body postures, has been proposed by clinicians and is taken into consideration when treating children with poor postural control and moderate to severe eating impairments. However, this relationship has not been rigorously investigated. The purpose of this study was to document the possible relationships among oral-motor, postural, and ambulatory control. Ambulatory skills [exclusive use of wheelchair (w/c) vs w/c and ambulation], postural control when sitting, "pathologic" reflexes, and lip and tongue posture were recorded before and after one year of therapy with an intraoral appliance (ISMAR) in 20 children with cerebral palsy and moderate eating impairment. Significant improvement occurred in sitting (head-trunk-foot control) following one year of ISMAR therapy. Ambulatory status also significantly improved above the level of maturation. Half of the children showed marked improvement in oral posture, i.e., their resting mouth posture was closed rather than open. These results support an hypothesis of interaction between oral structures and postural control of the "whole body." Further studies are needed to determine the controls of such a relationship.