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PURPOSE: We evaluated demographic, financial and support predictors of distress for parents of young children with disorders of sex development including atypical genital development, and characterized early parental experiences. This work extends our previous findings to identify those parents at risk for distress. MATERIALS AND METHODS: Participants included mothers (76) and fathers (63) of a child (78) diagnosed with disorders of sex development characterized by moderate to severe genital atypia. Parents completed a demographic questionnaire, measures of anxious and depressive symptoms, quality of life, illness uncertainty and posttraumatic stress symptoms, and rated their satisfaction with the appearance of their child's genitalia. RESULTS: Depressive and posttraumatic stress symptoms of caregivers were comparable to standardized norms while levels of anxious symptoms were below norms. A subset of parents reported clinically elevated symptoms. Overall 26% of parents reported anxious symptoms, 24% reported depressive symptoms and 17% reported posttraumatic stress symptoms. Levels of illness uncertainty were lower than those of parents of children with other chronic illnesses. Differences by parent sex emerged, with mothers reporting greater distress. Lower income, increased medical care and travel expenses, and having no other children were related to increased psychosocial distress. CONCLUSIONS: Early psychosocial screening is recommended for parents of children with disorders of sex development. Clinicians should be aware that financial burden and lack of previous parenting experience are risk factors for distress.
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Trastornos del Desarrollo Sexual/psicología , Padres/psicología , Calidad de Vida , Estrés Psicológico/etiología , Adulto , Preescolar , Trastornos del Desarrollo Sexual/complicaciones , Femenino , Humanos , Incidencia , Lactante , Masculino , Pronóstico , Factores de Riesgo , Estrés Psicológico/epidemiología , Estrés Psicológico/psicología , Estados Unidos/epidemiologíaRESUMEN
Objective: The purpose of this study was to assess clinical practice patterns with regard to diagnosis and management of testicular regression syndrome (TRS), a condition in 46,XY males with male phenotypic genitalia and bilateral absence of testes. Methods: A retrospective review was conducted at two large pediatric academic centers to examine diagnostic and management approaches for TRS. Results: Records of 57 patients were reviewed. Diagnostic methods varied widely between patients and included hormonal testing, karyotype, imaging, and surgical exploration, with multiple diagnostic methods frequently used in each patient. Of the 30 subjects that had reached adolescence at the time of the study, 17 (57%) had gaps in care of more than 5 years during childhood. Thirty subjects had received testosterone replacement therapy at a mean age of 12.1 ± 1.0 years. Forty-seven percent had a documented discussion of infertility. Eighty-two percent discussed prosthesis placement, with 35% having prostheses placed. Twenty-three percent were seen by a psychosocial provider. The between-site differences were age at fertility discussion, age at and number of prostheses placed, and type/age of testosterone initiation. Conclusion: Our findings highlight the wide variation in diagnostic approaches, follow-up frequency, testosterone initiation, fertility counseling, and psychosocial support for patients with TRS. Developing evidence-based guidelines for the evaluation and management of TRS would help reduce inconsistencies in care and unnecessary testing. Ongoing follow-up and coordination of care, even during the years when no hormonal treatment is being administered, could lead to opportunities for psychosocial support and improved interdisciplinary approach to care. Abbreviations: AMH = antimüllerian hormone; CAH = congenital adrenal hyperplasia; DSD = differences/disorders of sex development; hCG = human chorionic gonadotropin; TRS = testicular regression syndrome.
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Hiperplasia Suprarrenal Congénita , Disgenesia Gonadal 46 XY , Testículo/anomalías , Adolescente , Niño , Humanos , Masculino , Estudios RetrospectivosRESUMEN
PURPOSE OF REVIEW: Disorders of sex development (DSD) are a diverse group of conditions affecting gonadal development, sexual differentiation, or chromosomal sex. In this review, we will discuss recent literature on the genetic causes of DSD, with a focus on novel genetic sequencing technologies, new phenotypes associated with known DSD genes, and increasing recognition of the role of genetic regulatory elements in DSD. RECENT FINDINGS: We performed a comprehensive search of PubMed through August 2016 to identify important peer-reviewed publications from 2015 to 2016 on the topic of DSD genetics. SUMMARY: Whole-exome sequencing was used to successfully identify genetic causes of DSD in 35% of a cohort of 46,XY patients who had not previously received a genetic diagnosis. A novel mutation in NR5A1 has been identified as a cause of 46,XX testicular and ovotesticular DSD, demonstrating a previously unappreciated role of NR5A1 in preventing testicular differentiation in 46,XX individuals. Genetic regulatory elements of SOX9 have been identified as causes of 46,XX and 46,XY DSD.
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Trastornos del Desarrollo Sexual/genética , Secuenciación Completa del Genoma/tendencias , Humanos , FenotipoRESUMEN
Children with hepatoblastoma have an increased incidence of fractures, but data are limited. Previous reports document an average of 4 fractures per child with hepatoblastoma. We present a severe case of a premature 4-month-old with multiple fractures in the setting of Beckwith-Wiedemann syndrome and hepatoblastoma. Although prematurity is a known risk for metabolic bone disease, it did not entirely explain the severity. Our patient underwent chemotherapy and surgical resection of his hepatoblastoma. Once deemed stable, he received a dose of zoledronic acid (ZA). One month post treatment with ZA, a skeletal survey revealed healing of the rib and femoral fractures and no new fractures. Five months post ZA, the skeletal survey revealed no new fractures and motor development was appropriate. An extensive search revealed scant literature on the rate or cause of pathologic fractures in patients with newly diagnosed hepatoblastoma. A better understanding of fracture risk in this population may guide prevention strategies, screening, and treatment. In our case, prematurity and substantial chronic illness may have compounded the known fracture risk associated with hepatoblastoma and may provide insight into the pathophysiology and prevention of fractures in this setting.
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Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in early infancy. Mutations in the gene for heterozygous hepatocyte nuclear transcription factor 4-alpha (HNF4A) account for approximately 5% of cases and are inherited in an autosomal dominant fashion or arise as de novo mutations. This case describes a unique presentation of parental gonadal, or germline, mosaicism as the suspected inheritance pattern for siblings with congenital hyperinsulinism caused by HNF4A mutations. Two siblings presented with hypoglycemia in the first hours of life and were subsequently confirmed to have hyperinsulinism. In each patient, glycemic control was achieved at relatively low doses of diazoxide. Both siblings tested positive for the same HNF4A mutation, whereas the parents tested negative for HNF4A mutations. Gonadal, or germline, mosaicism became the presumed leading diagnosis, given 2 unaffected parents with 2 children with congenital hyperinsulinism. The older sibling demonstrated additional clinical features of liver disease and renal Fanconi syndrome, both of which are associated with HNF4A mutations. Genetic testing plays an important role in the diagnosis and management of congenital hyperinsulinism. HNF4A mutations may arise by a range of mechanisms, including gonadal, or germline, mosaicism. HNF4A mutations have phenotypic variance that may affect multiple organ systems at any age.
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Muscle atrophy, weakness, and loss of ambulation in the pediatric population are signs of progressive neuromuscular diseases. Rapid identification of such diseases is important to prevent further progression. In pediatric neurology, it is well understood to include neuromuscular disorders in the differential for such presentations. We report a case of severe nutritional rickets that mimicked the presentation of spinal muscular atrophy type III and discuss the importance of including rickets in the differential for muscle atrophy and loss of ambulation. A 33-month-old African American boy with several months of gait abnormality was referred to outpatient neurology. The initial diagnostic evaluation focused primarily on neuromuscular disorders, specifically SMA type III, given the absence of reflexes on examination and the history of prior ambulation. After an unfruitful genetic workup, it was elucidated that the child had very poor dietary intake and minimal sun exposure causing nutritional rickets that improved with intervention.
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Raquitismo , Atrofias Musculares Espinales de la Infancia , Niño , Masculino , Humanos , Preescolar , Atrofias Musculares Espinales de la Infancia/diagnóstico , Marcha , Caminata , Atrofia Muscular , Raquitismo/diagnósticoRESUMEN
INTRODUCTION: A central ethical dilemma in management of the patient with a disorder of sex development (DSD) is the potential conflict between respect for the fundamental right of the child for physical and emotional integrity and self-determination, and the right of parents to serve as surrogate decision-makers and act in their child's best interest. METHODS: Over the past 2 years we have encountered three complex DSD cases on the spectrum of mixed gonadal dysgenesis to ovotesticular DSD in which gender assignment and therefore optimal surgical management was uncertain. All patients had mosaic karyotypes with Y chromosome, dysgenetic ovary and dysgenetic testis, a urogenital sinus, and prominent phallus. In all three cases a team approach was taken to assess functional potential and risks along either gender pathway and to develop a spectrum of treatment options for parental consideration, including: 1. masculinization with removal of dysgenetic ovary; 2. initial vaginoplasty but with retention of the phallus (±bilateral gonadectomy); 3. initial vaginoplasty with "burial" of corporal bodies (Pippi Salle procedure) (±bilateral gonadectomy); 4. full feminization: vaginoplasty and clitoroplasty (with bilateral gonadectomy); 5. no surgical intervention. RESULTS: In all three cases, after consideration of risks and benefits of all options, parents selected option 2: gonadectomy to eliminate tumor risk and vaginoplasty, taking advantage of the child's young age to exteriorize urinary and reproductive tracts to avoid incontinence and infection and supporting parental bias toward female gender, but preservation of phallic structures to ensure a male option should the patient later declare a male gender identity. Parents of the three patients were contacted post-operatively (at 7, 17, and 22 months) for follow-up. All (3/3) regarded their child's development and wellbeing positively, and their own decisions regarding gender assignment and surgical plan favorably. All (3/3) regarded the team advisory process as balanced and supportive. CONCLUSION: In the setting of exposure of the neonatal brain to testosterone, vaginoplasty and phallic preservation afforded a balance between parental preferences and preservation of anatomic options, allowing potential reconstruction of male or female phenotype as gender identity is ascertained thereby respecting both parent and patient rights. Parents valued a spectrum of options, transparency, and the team decision-making process.
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Trastornos del Desarrollo Sexual/psicología , Trastornos del Desarrollo Sexual/cirugía , Condición Moral , Autonomía Personal , Actitud , Femenino , Humanos , Lactante , Padres/psicologíaRESUMEN
Disorders of sex development are challenging to evaluate and diagnose in the newborn. As pediatric urologists, our goals are to (1) identify patients who should be evaluated; (2) rule out life-threatening syndromes; and (3) involve a multidisciplinary team for evaluation, diagnosis, and gender assignment. This review briefly goes over the newborn differential diagnosis in disorders of sex development, highlights the important laboratory and imaging data needed, and discusses the multidisciplinary approach to gender assignment and care of these patients. Early involvement of the family in decision-making with the multidisciplinary team is paramount to a timely evaluation and diagnosis in these patients.
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Toma de Decisiones , Manejo de la Enfermedad , Trastornos del Desarrollo Sexual , Diferenciación Sexual , Diagnóstico Diferencial , Trastornos del Desarrollo Sexual/diagnóstico , Trastornos del Desarrollo Sexual/epidemiología , Trastornos del Desarrollo Sexual/terapia , Femenino , Identidad de Género , Salud Global , Humanos , Recién Nacido , Masculino , Morbilidad/tendenciasRESUMEN
BACKGROUND: A variant in steroidogenic factor-1 (SF-1, encoded by the gene NR5A1), p.Arg92Trp, has recently been reported in multiple families with 46,XX ovotesticular or testicular disorders of sex development (DSD). This amino acid change impacts the DNA-binding domain and perturbs gonadal differentiation pathways. METHODS: Whole-exome sequencing was performed on a 46,XX subject with ovotesticular DSD. RESULTS: Exome results identified a heterozygous NR5A1 variant, p.Arg92Gln, in the 46,XX ovotesticular DSD proband. This arginine-to-glutamine change has been previously reported in the homozygous state in a 46,XY patient with gonadal and adrenal dysgenesis, though 46,XY and 46,XX heterozygous carriers of this variant have not been previously reported to have any clinical phenotype. CONCLUSIONS: The NR5A1 p.Arg92Gln variant, which has thus far only been seen in a family with 46,XY DSD, most likely contributes to the ovotesticular DSD in this case. In light of the recent reports of unrelated 46,XX subjects with testicular or ovotesticular DSD with the NR5A1 variant p.Arg92Trp, it appears that other mutations in the DNA binding domain have the potential to impact the factors determining testicular and ovarian differentiation. This case demonstrates the variability of phenotypes with the same genotype and broadens our understanding of the role of SF-1 in gonadal differentiation.
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Trastornos del Desarrollo Sexual 46, XX/genética , Mutación Missense , Trastornos Ovotesticulares del Desarrollo Sexual/genética , Factor Esteroidogénico 1/genética , Trastornos del Desarrollo Sexual 46, XX/patología , Sustitución de Aminoácidos , Preescolar , Femenino , Humanos , Trastornos Ovotesticulares del Desarrollo Sexual/patología , Dominios ProteicosRESUMEN
BACKGROUND: Undervirilized 46,XY males with bifid scrotum often pose a diagnostic challenge, and the majority of cases typically do not receive a genetic diagnosis. NR5A1 mutations can be seen in 10-20% of the cases and are a relatively common cause of undervirilization. METHODS: Whole-exome sequencing was utilized to study 10 undervirilized 46,XY subjects with bifid scrotum. RESULTS: Exome sequencing identified novel NR5A1 variants, both affecting exon 7, in 2 of the 10 subjects with bifid scrotum. Subject 1 had a heterozygous frameshift variant, c.1150delC, p.Leu384fsTer1, within the ligand-binding domain inherited from his unaffected father. Subject 2 had a novel splice-site variant c.1139-2T>C, affecting the canonical splice acceptor site for exon 7 and also disrupting the ligand-binding domain. Both subjects had serum testosterone levels within the normal range as infants. CONCLUSIONS: We describe two novel NR5A1 variants, demonstrating mutations in this gene as a common cause of milder cases of 46,XY undervirilization. Whole-exome sequencing results yielded the diagnosis in 2 out of 10 cases without a previous diagnosis, supporting the value of this approach. Significant genotype-phenotype variability was also noted with Subject 1's paternal inheritance from his unaffected father.
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Trastornos del Desarrollo Sexual 46, XX , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Sitios de Empalme de ARN , Factor Esteroidogénico 1/genética , Testosterona/sangre , Trastornos del Desarrollo Sexual 46, XX/sangre , Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Trastornos del Desarrollo Sexual 46, XX/genética , Trastornos del Desarrollo Sexual 46, XX/patología , Humanos , Recién Nacido , MasculinoRESUMEN
CONTEXT: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. OBJECTIVE: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. PATIENTS AND METHODS: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. RESULTS: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. CONCLUSIONS: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
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Agrecanos/genética , Enanismo/genética , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antropometría/métodos , Braquidactilia/genética , Niño , Preescolar , Análisis Mutacional de ADN/métodos , Enanismo/tratamiento farmacológico , Femenino , Crecimiento/genética , Hormona del Crecimiento/uso terapéutico , Heterocigoto , Humanos , Lactante , Degeneración del Disco Intervertebral/genética , Desplazamiento del Disco Intervertebral/genética , Masculino , Persona de Mediana Edad , Osteocondritis Disecante/congénito , Osteocondritis Disecante/genética , Linaje , Fenotipo , Adulto JovenRESUMEN
OBJECTIVE: In response to the current CDC recommendations for routine HIV testing in clinical settings, the Adolescent AIDS Program at Montefiore Medical Center in the Bronx, New York, developed the Advise, Consent, Test, Support routine HIV testing model (ACTS) in 2003. ACTS was piloted in 10 community health centers operated by Montefiore because they serve populations most at risk for HIV/AIDS. METHODS: ACTS streamlined and codified the counseling and testing process, provided a routine HIV testing practice change plan, and provided training and communication materials that promoted routine HIV testing. To determine program success, we measured the number of patients seen at the clinics, the number of HIV test-eligible patients (those aged 13-64 years and not pregnant), the number and percent of patients receiving HIV testing, HIV test results, and the number of patients linked to care. RESULTS: HIV testing in the 10 sites increased nearly threefold during the pilot period (2003-2007), from 3,944 of 49,125 eligible patients (8%) tested in 2003 to 11,212 of 55,629 eligible patients (20%) tested in 2007. With little ongoing support, the sites continued or maintained improvements: 13,226 of 56,686 eligible patients (23%) were tested in 2008, 15,965 of 57,025 eligible patients (28%) were tested in 2011, 17,483 of 60,514 eligible patients (29%) were tested in 2012, and 17,971 of 63,172 eligible patients (28%) were tested in 2013. Sites identified 433 HIV-positive patients from 2006 to 2013 (0.2%-0.6% annual seropositivity), and 96% of them were linked to care within 90 days of HIV diagnoses (range: 92% to 98% annually). CONCLUSION: ACTS demonstrated that substantial and sustained increases in routine HIV testing can be achieved in health-care settings, not by adding personnel or financial resources, but by using the model's practice change plan and streamlined HIV testing approach.
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Serodiagnóstico del SIDA/métodos , Centros Comunitarios de Salud/organización & administración , Serodiagnóstico del SIDA/estadística & datos numéricos , Adolescente , Adulto , Centros Comunitarios de Salud/estadística & datos numéricos , Pruebas Diagnósticas de Rutina/métodos , Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Adulto JovenRESUMEN
Plasminogen activator inhibitor-2 (PAI-2) as a potential eosinophil protein was inferred from our gene microarray study of mouse eosinophilopoiesis. Here, we detect 47 kDa intracellular and approximately 60 kDa secretory forms of PAI-2 in purified human eosinophil extracts. PAI-2 is present at variable concentrations in eosinophil lysates, ranging from 30 to 444 ng/10(6) cells, with a mean of 182 ng/10(6) cells from 10 normal donors, which is the highest per-cell concentration among all leukocyte subtypes evaluated. Enzymatic assay confirmed that eosinophil-derived PAI-2 is biologically active and inhibits activation of its preferred substrate, urokinase. Immunohistochemical and immunogold staining demonstrated PAI-2 localization in eosinophil-specific granules. Immunoreactive PAI-2 was detected in extracellular deposits in and around the eosinophil-enriched granuloma tissue encapsulating the parasitic egg in livers of wild-type mice infected with the helminthic parasite Schistosoma mansoni. Among the possibilities, we consider a role for eosinophil-derived PAI-2 in inflammation and remodeling associated with parasitic infection as well as allergic airways disease, respiratory virus infection, and host responses to tumors and metastasis in vivo.
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Eosinófilos/inmunología , Inhibidor 2 de Activador Plasminogénico/metabolismo , Schistosoma mansoni/patogenicidad , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Animales , Médula Ósea/metabolismo , Médula Ósea/patología , Eosinófilos/parasitología , Granuloma/parasitología , Humanos , Interleucina-5/genética , Interleucina-5/fisiología , Hígado/parasitología , Ratones , Óvulo/parasitologíaAsunto(s)
Citas y Horarios , Medicina Familiar y Comunitaria/organización & administración , Necesidades y Demandas de Servicios de Salud/organización & administración , Gestión de la Práctica Profesional/organización & administración , Centros Médicos Académicos/organización & administración , Continuidad de la Atención al Paciente/organización & administración , Accesibilidad a los Servicios de Salud/organización & administración , Humanos , Modelos Organizacionales , Cooperación del Paciente , Atención Dirigida al Paciente/organización & administración , Estados Unidos , Listas de EsperaRESUMEN
BACKGROUND: Cockayne syndrome is an autosomal recessive, heterogeneous syndrome with classical features, including short stature, microcephaly, developmental delay, neuropathy, and photosensitivity. New genomic approaches offer improved molecular diagnostic potential. METHODS: Whole-exome sequencing was employed to study a consanguineous extended family with severe short stature and variable presentations of peripheral neuropathy, lipoatrophy, photosensitivity, webbed neck, and hirsutism. RESULTS: We identified a novel homozygous ERCC6 variant at the donor splice site of intron 9 (c.1992 + 3A>G), which was predicted to only slightly perturb splicing efficiencies. Assessment of primary fibroblast-derived mRNAs, however, revealed a dominant splicing species that utilized an unsuspected putative donor splice site within exon 9, resulting in predicted early protein termination (p.Arg637Serfs*34). CONCLUSIONS: We describe a new splicing ERCC6 defect causal of Cockayne syndrome. The application of exome sequence analysis was integral to diagnosis, given the complexity of phenotypic presentation in the affected family members. The novel splicing defect, furthermore, illustrates how a seemingly minor change in the relative strength of a splice site can have significant biological consequences.
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Síndrome de Cockayne/genética , Codón de Terminación/genética , ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Mutación Puntual , Sitios de Empalme de ARN/genética , Empalme del ARN/genética , Síndrome de Cockayne/diagnóstico , Exoma , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Proteínas de Unión a Poli-ADP-RibosaRESUMEN
A critical role for eosinophils in remodeling of allergic airways was observed in vivo upon disruption of the dblGATA enhancer that regulates expression of GATA-1, which resulted in an eosinophil-deficient phenotype in the DeltadblGATA mouse. We demonstrate here that bone marrow progenitors isolated from DeltadblGATA mice can differentiate into mature eosinophils when subjected to cytokine stimulation ex vivo. Cultured DeltadblGATA eosinophils contain cytoplasmic granules with immunoreactive major basic protein and they express surface Siglec F and transcripts encoding major basic protein, eosinophil peroxidase, and GATA-1, -2, and -3 to an extent indistinguishable from cultured wild-type eosinophils. Fibroblast coculture and bone marrow cross-transplant experiments indicate that the in vivo eosinophil deficit is an intrinsic progenitor defect, and remains unaffected by interactions with stromal cells. Interestingly, and in contrast to those from the wild type, a majority of the GATA-1 transcripts from cultured DeltadblGATA progenitors express a variant GATA-1 transcript that includes a first exon (1E(B)), located approximately 3700 bp downstream to the previously described first exon found in hemopoietic cells (1E(A)) and approximately 42 bp upstream to another variant first exon, 1E(C). These data suggest that cultured progenitors are able to circumvent the effects of the DeltadblGATA ablation by using a second, more proximal, promoter and use this mechanism to generate quantities of GATA-1 that will support eosinophil growth and differentiation.
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Células de la Médula Ósea/inmunología , Diferenciación Celular/genética , Linaje de la Célula/genética , Elementos de Facilitación Genéticos , Eosinófilos/metabolismo , Factor de Transcripción GATA1/genética , Células Madre Hematopoyéticas/inmunología , Regiones Promotoras Genéticas/inmunología , Animales , Sitios de Unión/genética , Sitios de Unión/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Eosinófilos/citología , Eosinófilos/inmunología , Eosinófilos/trasplante , Factor de Transcripción GATA1/fisiología , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA3/genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Interleucina-5/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Mutantes , Células Th2/inmunologíaRESUMEN
We explore the controversial issue of the role of eosinophils in host defense against helminthic parasites using the established Schistosoma mansoni infection model in 2 novel mouse models of eosinophil lineage ablation (DeltadblGATA and TgPHIL). No eosinophils were detected in bone marrow of infected DeltadblGATA or TgPHIL mice, despite the fact that serum IL-5 levels in these infected mice exceeded those in infected wild type by approximately 4-fold. Liver granulomata from infected DeltadblGATA and TgPHIL mice were likewise depleted of eosinophils compared with those from their respective wild types. No eosinophil-dependent differences in granuloma number, size, or fibrosis were detected at weeks 8 or 12 of infection, and differential accumulation of mast cells was observed among the DeltadblGATA mice only at week 12. Likewise, serum levels of liver transaminases, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) increased in all mice in response to S mansoni infection, with no eosinophil-dependent differences in hepatocellular damage observed. Finally, eosinophil ablation had no effect on worm burden or on egg deposition. Overall, our data indicate that eosinophil ablation has no impact on traditional measures of disease in the S mansoni infection model in mice. However, eosinophils may have unexplored immunomodulatory contributions to this disease process.
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Granuloma/parasitología , Schistosoma mansoni/metabolismo , Esquistosomiasis mansoni/sangre , Animales , Células de la Médula Ósea/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linaje de la Célula , Eosinófilos/patología , Granuloma/metabolismo , Interleucina-5/biosíntesis , Interleucina-5/sangre , Hígado/metabolismo , Masculino , Mastocitos/metabolismo , Mastocitos/parasitología , Ratones , Ratones Endogámicos BALB C , Células Th2/metabolismoRESUMEN
On July 31, 2001, the U.S. House of Representatives passed The Human Cloning Prohibition Act of 2001. The legislation proposes a complete ban on somatic cell nuclear transfer to create cloned human embryos; it threatens transgressors with criminal punishment and civil fines. House Bill 2505 is the first human cloning prohibition to pass either chamber of Congress. This note argues that the bill is unconstitutionally vague and inconsistent with the Supreme Court's recent Commerce Clause jurisprudence.