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1.
Br J Haematol ; 195(4): 621-628, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34396511

RESUMEN

We previously found that neurodevelopmental deficits commonly occurred in three-year-olds with sickle cell disease (SCD), but clinical significance was uncertain because a comparison group was lacking. Our objective in the current study was to prospectively compare neurodevelopment in three-year-old children with SCD to an age-appropriate control group. The Brigance Preschool Screen II is a neurodevelopmental screening examination which can be administered in 15-20 min. SCD patients (Group 1) were compared with community controls of similar age and ethnicity enrolled in daycare/preschool (Group 2). SCD patients who were receiving hydroxycarbamide treatment were also compared (Group 3). Two hundred forty-five three-year-olds were evaluated: Group 1, 111; Group 2, 114; and Group 3, 20. The below cut-off rate on the Brigance test was higher in Group 1 (73%) than in Group 2 (61%; P = 0·04). In multivariate analysis of Group 1 patients, only lower household income and more persons living in the home were independent predictors of this. Patients with SCD and matched controls had high rates of 'failing' the Brigance test. The below cut-off rate in untreated children with SCD was associated with low household income and increased number of persons living in the home.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Tamizaje Masivo , Trastornos del Neurodesarrollo/etiología , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/epidemiología , Antidrepanocíticos/uso terapéutico , Preescolar , Composición Familiar , Femenino , Humanos , Hidroxiurea/uso terapéutico , Renta , Masculino , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/epidemiología , Pruebas Neuropsicológicas , Estudios Prospectivos , Determinantes Sociales de la Salud
2.
Pediatr Blood Cancer ; 66(7): e27717, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30907497

RESUMEN

Elevated tricuspid valve regurgitation jet velocity (TRV ≥ 2.5 m/s) is associated with mortality among adults with sickle cell disease (SCD), but correlative biomarkers are not studied according to treatment exposure or genotypes. To investigate the associations between biomarkers and TRV elevation, we examined the relationship between TRV and hemolytic, inflammatory, and cardiac biomarkers, stratified by disease-modifying treatments and SCD genotype. In total, 294 participants with SCD (mean age, 11.0 ± 3.7 years) and 49 hereditary spherocytosis (HS; mean age, 22.9 ± 19.75 years) were included for comparison and enrolled. TRV was elevated in 30.7% of children with SCD overall: 18.8% in HbSC/HbSß+ -thalassemia, 28.9% in untreated HbSS/HbSß0 -thalassemia, 34.2% in HbSS/HbSß0 -thalassemia hydroxyurea-treated, and 57% in HbSS/HbSß0 -thalassemia chronic transfusion treated. TRV was elevated in 10.7% and 27.8% in HS children and adults, respectively. In children with SCD, elevated TRV was correlated with hemoglobin (odds ratio [OR] = 0.78, P = 0.004), lactate dehydrogenase (LDH; OR = 2.52, P = 0.005), and N-terminal pro-brain natriuretic peptide (NT-pro BNP; OR = 1.003, P = 0.004). In multivariable logistic regression, adjusting for genotype, sex, hemolytic index, and treatment, hemoglobin concentration remained the only significant variable associated with elevated TRV in untreated HbSS/HbSß0 -thalassemia participants. TRV was not associated with inflammatory markers, other markers of hemolysis, or NT-pro BNP in untreated HbSS/HbSß0 -thalassemia. Neither hemoglobin nor LDH was associated with TRV in HbSC/HbSß+ -thalassemia. These results suggest that elevated TRV is influenced by the degree of anemia, possibly reflecting sickling as part of the disease pathophysiology. Prospective studies should monitor hemoglobin concentration as children with SCD age into adulthood, prompting initiation of TRV screening and monitoring.


Asunto(s)
Anemia de Células Falciformes , Insuficiencia de la Válvula Tricúspide , Talasemia beta , Adolescente , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/fisiopatología , Niño , Preescolar , Femenino , Humanos , Masculino , Prevalencia , Insuficiencia de la Válvula Tricúspide/complicaciones , Insuficiencia de la Válvula Tricúspide/tratamiento farmacológico , Insuficiencia de la Válvula Tricúspide/epidemiología , Insuficiencia de la Válvula Tricúspide/fisiopatología , Talasemia beta/complicaciones , Talasemia beta/tratamiento farmacológico , Talasemia beta/epidemiología , Talasemia beta/fisiopatología
3.
Br J Haematol ; 183(5): 796-806, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30450553

RESUMEN

Cardiac disease is the primary cause of death in sickle cell disease (SCD). Right and left ventricular global longitudinal strain (RVGLS, LVGLS) are early markers of systolic dysfunction but are not well investigated among children with SCD. One hundred and forty-three patients with HbSS or HbSß0 -thalassaemia (median age 11 years, range 5-19 years) and 71 controls matched for age and sex were compared. RVGLS and LVGLS were measured and compared with conventional measures of echocardiography and markers of haemolysis and inflammation. RVGLS was higher in children with SCD than in controls (-25·72% ± 3·45% vs. -24·54% ± 2·41%, P = 0·005); LVGLS was not different. RVGLS decreased with older age in children with SCD (ρ = 0·338, P < 0·001) but not among controls. Decreased RVGLS was associated with increased left atrial end diastolic volume (ρ = 0·181, P = 0·04); RVGLS increased with cardiac output (r = -0·279, P = 0·01). RVGLS and LVGLS were not associated with disease-modifying therapies, degree of anaemia or haemolysis markers. Elevated RVGLS may indicate an early RV compensatory mechanism in response to upstream myocardial insults and elevated cardiac output. Global longitudinal strain may serve as an early marker of altered myocardial function in children with SCD.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Corazón/fisiología , Disfunción Ventricular Izquierda/etiología , Adolescente , Anemia de Células Falciformes/fisiopatología , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Ecocardiografía , Femenino , Ventrículos Cardíacos , Humanos , Masculino , Estrés Fisiológico/fisiología , Volumen Sistólico/fisiología , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/fisiopatología , Adulto Joven
4.
Br J Clin Pharmacol ; 84(7): 1478-1485, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-28884840

RESUMEN

AIMS: The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew ) vs. those receiving chronic therapy (HCchronic ), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements. METHODS: Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration vs. time profiles were evaluated with a model independent approach in the HCnew and HCchronic groups. Various predictive scenarios were analysed to evaluate whether systemic exposure with hydroxycarbamide could be accurately predicted. RESULTS: Absorption of hydroxycarbamide was rapid, variable and dose independent. Dose-normalized peak plasma concentrations and drug exposure (AUC) were higher, and weight-normalized apparent oral clearance was lower in the HCnew group. We assessed a PK-guided dosing strategy along with other predictive scenarios and found that inclusion of plasma samples only slightly improved the accuracy of AUC predictions when compared to a population-based method. CONCLUSIONS: Children naïve to hydroxycarbamide exhibit a different PK profile compared to children receiving chronic therapy. Accuracy of population-based dosing is sufficient to target AUCs in individual patients. Further clearance/bioavailability studies are needed to address the factors responsible for variability in the disposition of hydroxycarbamide.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/farmacocinética , Hidroxiurea/farmacocinética , Modelos Biológicos , Adolescente , Anemia de Células Falciformes/sangre , Antidrepanocíticos/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Hidroxiurea/administración & dosificación , Masculino , Estudios Prospectivos
5.
Transpl Infect Dis ; 20(1)2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29178554

RESUMEN

BACKGROUND: T-cell depletion (TCD) effectively reduces severe graft-versus-host disease in recipients of HLA-mismatched allografts. However, TCD is associated with delayed immune recovery and increased infections. We hypothesized that specific depletion of CD45RA+ naive T cells, rather than broad depletion of CD3+ T cells, can preserve memory-immunity in the allografts and confer protection against important viral infections in the early post-transplant period. METHODS: Sixty-seven patients who received TCD haploidentical donor transplantation for hematologic malignancy on 3 consecutive trials were analyzed. RESULTS: Patients receiving CD45RA-depleted donor grafts had 2000-fold more donor T cells infused, significantly higher T-cell counts at Day +30 post transplant (550/µL vs 10/µL; P < .001), and higher T-cell diversity by Vbeta spectratyping at Day +100 (P < .001). Importantly, these recipients experienced a significant reduction in both the incidence (P = .002) and duration (P = .02) of any viremia (cytomegalovirus, Epstein-Barr virus, or adenovirus) in the first 6 months post transplant. Specifically, recipients of CD3-depleted grafts were more likely to experience adenovirus viremia (27% vs 4%, P = .02). CONCLUSION: CD45RA-depletion provided a large number of donor memory T cells to the recipients and was associated with enhanced early T-cell recovery and protection against viremia.


Asunto(s)
Donantes de Sangre , Complejo CD3/inmunología , Antígenos Comunes de Leucocito/inmunología , Depleción Linfocítica , Linfocitos T/inmunología , Viremia/prevención & control , Adolescente , Niño , Preescolar , Femenino , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas , Herpesvirus Humano 6/inmunología , Humanos , Memoria Inmunológica , Lactante , Masculino , Infecciones por Roseolovirus/prevención & control , Infecciones por Roseolovirus/virología , Trasplante Haploidéntico , Trasplante Homólogo/efectos adversos , Viremia/inmunología , Adulto Joven
6.
Lancet Oncol ; 17(12): 1709-1719, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27743922

RESUMEN

BACKGROUND: Patients with peritoneal metastatic colorectal cancer have reduced overall survival compared with patients with metastatic colorectal cancer without peritoneal involvement. Here we further investigated the effect of the number and location of metastases in patients receiving first-line systemic chemotherapy. METHODS: We analysed individual patient data for previously untreated patients enrolled in 14 phase 3 randomised trials done between 1997 and 2008. Trials were included if protocols explicitly pre-specified and solicited for patients with peritoneal involvement in the trial data collection process or had done a formal peritoneum-focused review of individual pre-treatment scans. We used stratified multivariable Cox models to assess the prognostic associations of peritoneal metastatic colorectal cancer with overall survival and progression-free survival, adjusting for other key clinical-pathological factors (age, sex, Eastern Cooperative Oncology Group (ECOG) performance score, primary tumour location [colon vs rectum], previous treatment, and baseline BMI). The primary endpoint was difference in overall survival between populations with and without peritoneal metastases. FINDINGS: Individual patient data were available for 10 553 patients. 9178 (87%) of 10 553 patients had non-peritoneal metastatic colorectal cancer (4385 with one site of metastasis, 4793 with two or more sites of metastasis), 194 (2%) patients had isolated peritoneal metastatic colorectal cancer, and 1181 (11%) had peritoneal metastatic colorectal cancer and other organ involvement. These groups were similar in age, ethnic origin, and use of targeted treatment. Patients with peritoneal metastatic colorectal cancer were more likely than those with non-peritoneal metastatic colorectal cancer to be women (565 [41%] of 1371 vs 3312 [36%] of 9169 patients; p=0·0003), have colon primary tumours (1116 [84%] of 1334 patients vs 5603 [66%]; p<0·0001), and have performance status of 2 (136 [10%] vs 521 [6%]; p<0·0001). We recorded a higher proportion of patients with mutated BRAF in patients with peritoneal-only (eight [18%] of 44 patients with available data) and peritoneal metastatic colorectal cancer with other sites of metastasis (34 [12%] of 289), compared with patients with non-peritoneal metastatic colorectal cancer (194 [9%] of 2230; p=0·028 comparing the three groups). Overall survival (adjusted HR 0·75, 95% CI 0·63-0·91; p=0·003) was better in patients with isolated non-peritoneal sites than in those with isolated peritoneal metastatic colorectal cancer. Overall survival of patients with two of more non-peritoneal sites of metastasis (adjusted HR 1·04, 95% CI 0·86-1·25, p=0.69) and those with peritoneal metastatic colorectal cancer plus one other site of metastasis (adjusted HR 1·10, 95% CI 0·89-1·37, p=0·37) was similar to those with isolated peritoneal metastases. Compared with patients with isolated peritoneal metastases, those with peritoneal metastases and two or more additional sites of metastasis had the shortest survival (adjusted HR 1·40; CI 1·14-1·71; p=0·0011). INTERPRETATION: Patients with peritoneal metastatic colorectal cancer have significantly shorter overall survival than those with other isolated sites of metastases. In patients with several sites of metastasis, poor survival is a function of both increased number of metastatic sites and peritoneal involvement. The pattern of metastasis and in particular, peritoneal involvement, results in prognostic heterogeneity of metastatic colorectal cancer. FUNDING: None.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Neoplasias Peritoneales/secundario , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos
7.
Br J Haematol ; 175(2): 331-338, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27604981

RESUMEN

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long-term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1-17·3) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P < 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3- to 6-year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Infarto Encefálico/diagnóstico por imagen , Infarto Encefálico/etiología , Hidroxiurea/uso terapéutico , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Adolescente , Anemia de Células Falciformes/diagnóstico , Enfermedades Asintomáticas , Niño , Preescolar , Femenino , Hemoglobina Fetal/genética , Humanos , Lactante , Masculino , Resultado del Tratamiento
8.
J Pediatr Surg ; 56(4): 754-759, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32690290

RESUMEN

PURPOSE: To identify factors associated with firearm injury (FI) and willingness to enroll in a violence intervention program amongst pediatric victims of violence. METHODS: Cross-sectional study of victims of violence age 6-19 years presenting to a children's hospital emergency department from 2014 to 2017. Participants were interviewed by social workers prior to being offered enrollment in a violence intervention program. We used multivariate logistic regression analyses to identify factors associated with FI and enrollment in the violence intervention program. RESULTS: Four hundred seven patients were analyzed, 156 (38%) of which were victims of FI and 251 (62%) were victims of non-firearm-related physical assaults (PA). Multiple factors were associated with FI including older adolescent age, male sex, separated/divorced parents, losses in family/social network due to violence, being on probation, illicit substance use, gang affiliation, and lack of school enrollment. One hundred four patients (26%) enrolled in the violence intervention program. There was no difference in enrollment between FI and PA. However, older adolescent age, illicit substance use and probation were associated with significantly decreased odds of enrolling in the program. CONCLUSIONS: Multiple identifiable and potentially actionable risk factors exist amongst pediatric victims of acute FI. More specific targeting of at-risk groups may improve enrollment in violence interventions programs. LEVEL OF EVIDENCE: This is a prognostic study, investigating the natural history of pediatric firearm injuries, factors associated with firearm injuries as well as those associated with patient propensity to enroll in a violence intervention program. This study is observational in nature and utilizes patients with non-firearm-related physical assaults as a control group, making this study Level III evidence.


Asunto(s)
Armas de Fuego , Heridas por Arma de Fuego , Adolescente , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Factores de Riesgo , Violencia , Heridas por Arma de Fuego/epidemiología , Adulto Joven
9.
J Allergy Clin Immunol Pract ; 8(1): 176-185.e2, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31371165

RESUMEN

BACKGROUND: Symptom-based adjustment (SBA) of inhaled corticosteroids may be an alternative patient-centered approach in which day-to-day inhaled corticosteroid use is adjusted by symptoms and short-acting ß-agonist need. OBJECTIVE: To evaluate the effectiveness of SBA in the primary care setting. METHODS: We conducted a randomized, open-label, pragmatic equivalence trial in African-American children (6-17 years old) with mild asthma managed by 12 primary care providers (PCPs). A total of 206 participants were randomized to SBA (as-needed beclomethasone 80 µg with rescue short-acting ß-agonist) or provider-based guideline-directed adjustment (PBA): maintenance beclomethasone 80 µg/d (6-11 years old), 160 µg/d (12-17 years old), with subsequent guideline-based dose adjustment by PCPs. PCPs implemented both treatment assignments, with outcomes measured by blinded staff. All participants received symptom recognition and albuterol use education from peer educators. Primary outcome was change in asthma control (measured by Asthma Control Test [ACT]/childhood ACT [cACT]) over 12 months. RESULTS: Participants had adequately controlled asthma (mean ACT or cACT score = 21.6 ± 2.8) at baseline. After 1 year, there was no significant between-group difference in change in ACT scores (SBA - PBA): ACT: -0.88 (95% CI, -2.19 to 0.42), cACT: -0.73 (-2.09 to 0.62), or combined ACT and cACT (P = .10), and was within the predefined statistical clinical equivalence. The proportion with an exacerbation and measures of lung function were similar between groups. Compared with PBA, SBA led to less beclomethasone use (SBA: 526 µg/mo [95% CI, 412-639 µg] vs PBA: 1961 µg/mo [95% CI, 1681-2241]; P < .0001). More parents in the SBA arm felt they were managing their child's asthma. CONCLUSIONS: SBA in African-American children with mild asthma was similar to PBA in asthma control and events when implemented by PCPs with lower inhaled corticosteroid exposure.


Asunto(s)
Antiasmáticos , Asma , Administración por Inhalación , Adolescente , Corticoesteroides/uso terapéutico , Negro o Afroamericano , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/epidemiología , Niño , Humanos
10.
J Am Coll Surg ; 227(4): 439-449, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30077861

RESUMEN

BACKGROUND: Pediatric short bowel syndrome (SBS) is a malabsorptive state placing patients at risk for malnutrition, dehydration, and bacterial overgrowth. These patients are often dependent on parenteral nutrition (PN) while intestinal adaptation is underway. The aim of this study was to characterize the effect of remnant small bowel length on the gut microbiome. Further, we sought to examine the contribution of clinical and nutritional variables to the gut microbiota and anthropometric growth. STUDY DESIGN: Clinical data, anthropometrics, and fecal samples were collected from 14 SBS patients and 10 age- and sex-matched controls. Fecal bacterial DNA composition was analyzed using 16s ribosomal RNA gene sequencing. Statistical analysis was completed using the Mann-Whitney or Fisher's exact tests when applicable and linear mixed effect modeling. RESULTS: Distinct microbiota changes were found among those with the least remaining small bowel (<35 cm) compared with those with longer remaining bowel and controls. Those with <35 cm small bowel displayed an increased relative abundance of Proteobacteria, while those with longer remaining small bowel had a higher proportion of Firmicutes. Further, patients with less remaining bowel required more PN (p < 0.01), with a tendency to be shorter in height (p = 0.05) and with a higher BMI (p = 0.05). CONCLUSIONS: Remnant small bowel length appears to be a predictor of stunting with diminished linear growth, parenteral nutrition dependency, and a greater relative abundance of Proteobacteria in the gut. These findings suggest an integrated adaptive response predicted by remnant intestinal length. Further research is necessary to examine the effects of intestinal dysbiosis on clinical outcomes.


Asunto(s)
Disbiosis/etiología , Disbiosis/microbiología , Microbioma Gastrointestinal , Intestino Delgado/microbiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/microbiología , Síndrome del Intestino Corto/cirugía , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino
11.
Neuroimage Clin ; 20: 913-922, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30308377

RESUMEN

Altered brain development is a common feature of the neurological sequelae of complex congenital heart disease (CHD). These alterations include abnormalities in brain size and growth that begin prenatally and persist postnatally. However, the longitudinal trajectory of changes in brain volume from the prenatal to postnatal environment have not been investigated. We aimed to evaluate the trajectory of brain growth in a cohort of patients with complex CHD (n = 16) and healthy controls (n = 15) to test the hypothesis that patients with complex CHD would have smaller total brain volume (TBV) prenatally, which would become increasingly prominent by three months of age. Participants underwent fetal magnetic resonance imaging (MRI) at a mean of 32 weeks gestation, a preoperative/neonatal MRI shortly after birth, a postoperative MRI (CHD only), and a 3-month MRI to evaluate the trajectory of brain growth. Three-dimensional volumetric analysis was applied to the MRI data to measure TBV, as well as tissue-specific volumes of the cortical gray matter (CGM), white matter (WM), subcortical (deep nuclear) gray matter (SCGM), cerebellum, and cerebrospinal fluid (CSF). A random coefficients model was used to investigate longitudinal changes in TBV and demonstrated an altered trajectory of brain growth in the CHD population. The estimated slope for TBV from fetal to 3-month MRI was 11.5 cm3 per week for CHD infants compared to 16.7 cm3 per week for controls (p = 0.0002). Brain growth followed a similar trajectory for the CGM (p < 0.0001), SCGM (p = 0.002), and cerebellum (p = 0.005). There was no difference in growth of the WM (p = 0.30) or CSF (p = 0.085). Brain injury was associated with reduced TBV at 3-month MRI (p = 0.02). After removing infants with brain injury from the model, an altered trajectory of brain growth persisted in CHD infants (p = 0.006). These findings extend the existing literature by demonstrating longitudinal impairments in brain development in the CHD population and emphasize the global nature of disrupted brain growth from the prenatal environment through early infancy.


Asunto(s)
Lesiones Encefálicas/patología , Sustancia Gris/crecimiento & desarrollo , Cardiopatías Congénitas/complicaciones , Sustancia Blanca/crecimiento & desarrollo , Adulto , Factores de Edad , Lesiones Encefálicas/complicaciones , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino
12.
J Exp Med ; 213(3): 433-49, 2016 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-26880577

RESUMEN

Understanding the molecular regulation of hematopoietic stem and progenitor cell (HSPC) engraftment is paramount to improving transplant outcomes. To discover novel regulators of HSPC repopulation, we transplanted >1,300 mice with shRNA-transduced HSPCs within 24 h of isolation and transduction to focus on detecting genes regulating repopulation. We identified 17 regulators of HSPC repopulation: Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251. Knockdown of each of these genes yielded a loss of function, except in the cases of Armcx1 and Gprasp2, whose loss enhanced hematopoietic stem cell (HSC) repopulation. The discovery of multiple genes regulating vesicular trafficking, cell surface receptor turnover, and secretion of extracellular matrix components suggests active cross talk between HSCs and the niche and that HSCs may actively condition the niche to promote engraftment. We validated that Foxa3 is required for HSC repopulating activity, as Foxa3(-/-) HSC fails to repopulate ablated hosts efficiently, implicating for the first time Foxa genes as regulators of HSPCs. We further show that Foxa3 likely regulates the HSC response to hematologic stress. Each gene discovered here offers a window into the novel processes that regulate stable HSPC engraftment into an ablated host.


Asunto(s)
Estudios de Asociación Genética , Células Madre Hematopoyéticas/citología , Secuencias de Aminoácidos , Animales , Proliferación Celular , Citoprotección , Elementos de Facilitación Genéticos/genética , Pruebas Genéticas , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas , Factor Nuclear 3-gamma del Hepatocito/metabolismo , Ratones Endogámicos C57BL , Unión Proteica , Reproducibilidad de los Resultados , Transducción de Señal , Estrés Fisiológico
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