RESUMO
Viral vector-mediated gene transfer to the postnatal respiratory epithelium has, in general, been of low efficiency due to physical and immunological barriers, non-apical location of cellular receptors critical for viral uptake and limited transduction of resident stem/progenitor cells. These obstacles may be overcome using a prenatal strategy. In this study, HIV-1-based lentiviral vectors (LVs) pseudotyped with the envelope glycoproteins of Jaagsiekte sheep retrovirus (JSRV-LV), baculovirus GP64 (GP64-LV), Ebola Zaire-LV or vesicular stomatitis virus (VSVg-LV) and the adeno-associated virus-2/6.2 (AAV2/6.2) were compared for in utero transfer of a green fluorescent protein (GFP) reporter gene to ovine lung epithelium between days 65 and 78 of gestation. GFP expression was examined on day 85 or 136 of gestation (term is â¼145 days). The percentage of the respiratory epithelial cells expressing GFP in fetal sheep that received the JSRV-LV (3.18 × 10(8)-6.85 × 10(9) viral particles per fetus) was 24.6±0.9% at 3 weeks postinjection (day 85) and 29.9±4.8% at 10 weeks postinjection (day 136). Expression was limited to the surface epithelium lining fetal airways <100 µm internal diameter. Fetal airways were amenable to VSVg-LV transduction, although the percentage of epithelial expression was low (6.6±0.6%) at 1 week postinjection. GP64-LV, Ebola Zaire-LV and AAV2/6.2 failed to transduce the fetal ovine lung under these conditions. These data demonstrate that prenatal lung gene transfer with LV engineered to target apical surface receptors can provide sustained and high levels of transgene expression and support the therapeutic potential of prenatal gene transfer for the treatment of congenital lung diseases.
Assuntos
Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Proteínas de Fluorescência Verde/metabolismo , Retrovirus Jaagsiekte de Ovinos/genética , Pulmão/embriologia , Ovinos/genética , Animais , Baculoviridae/genética , Dependovirus/genética , Ebolavirus/genética , Feto , Células HEK293 , Humanos , Hialuronoglucosaminidase/genética , Hialuronoglucosaminidase/metabolismo , Lentivirus/genética , Pulmão/crescimento & desenvolvimento , Mucosa Respiratória/crescimento & desenvolvimento , Mucosa Respiratória/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismoRESUMO
The three midline malformation complexes, the oral-facial-digital syndrome type VI (OFDS VI) or Váradi syndrome, the hydrolethalus syndrome (HS), and the Pallister-Hall syndrome (PHS) have been described as distinct genetic entities. Here, we report a fetus with a combination of clinical findings of all 3 syndromes similar to the twin fetuses described in the accompanying paper (Hingorani et al., 1991). The phenotypic overlap in these fetuses with the OFDS VI, HS, and PHS raises the question as to whether or not they indeed represent separate genetic entities as previously assumed.
Assuntos
Anormalidades Múltiplas/genética , Disostoses/complicações , Síndromes Orofaciodigitais/complicações , Disostoses/genética , Feto/anormalidades , Humanos , Hidrocefalia/complicações , Hidrocefalia/genética , Masculino , Síndromes Orofaciodigitais/classificação , Síndromes Orofaciodigitais/genética , Fenótipo , SíndromeRESUMO
Down syndrome (DS) is not usually thought of in association with significant infantile liver disease. We present clinical and histopathologic data from 10 patients with DS who presented with severe liver disease at birth or within the first few weeks of life, and summarize the findings of eight previously reported cases. The liver disease was fatal in all but one case. Diffuse lobular fibrosis surrounding proliferating ductular elements and residual hepatocytes characterized the pathologic findings in the liver in all patients. A large number of megakaryocytes were present in the liver in nine of 12 patients. The phenotype of "perinatal hemochromatosis" was documented in eight of nine cases in which the presence of iron was investigated. Since only a fraction of the patients with this phenotype have DS, the patients we describe seem to represent a relatively well-defined subset of the perinatal hemochromatosis phenotype. The existence of such a subset suggests that the perinatal hemochromatosis phenotype does not represent a single etiopathogenetic disorder. The association between DS, megakaryocytic infiltrates in the liver, and fatal subacute/chronic liver disease gives rise to the speculation that fibrosis-promoting factors and/or metabolic abnormalities, such as those resulting from a gene dosage effect, may play a role in the genesis of the liver disease, perhaps due to a particular susceptibility of fetal liver.
Assuntos
Síndrome de Down/complicações , Síndrome de Down/patologia , Hepatopatias/complicações , Hepatopatias/patologia , Feminino , Humanos , Recém-Nascido , Hepatopatias/congênito , MasculinoRESUMO
We describe a case in which an extensive sub-aortic infundibulum was accompanied by a muscular ventricular defect in the presence of a normal relationship of the great arteries. First impressions suggested that the ventriculo-arterial connexion was concordant, but sectioning the heart showed it to be double outlet from the right ventricle. It is important to identify this combination of features prior to attempted surgical correction, since the potentially restrictive sub-aortic infundibulum may not be visualised if the heart is approached surgically from the right ventricle. If unrelieved in the repair process, this could leave severe sub-aortic stenosis.
Assuntos
Valva Aórtica/anormalidades , Comunicação Interventricular/patologia , Ventrículos do Coração/anormalidades , Valva Mitral/anormalidades , Valva Aórtica/patologia , Feminino , Ventrículos do Coração/patologia , Humanos , Recém-Nascido , Valva Mitral/patologiaRESUMO
A variety of arterial lesions in both pulmonary and systemic circulations have been described in association with human immunodeficiency virus infection. Such lesions include plexogenic arteriopathy in patients with primary pulmonary hypertension and fibrocalcific arterial lesions described in a variety of organs. Lesions involving the pulmonary veins, however, have not been previously described. We report a case of pulmonary veno-occlusive disease in a 2-year-old child with human immunodeficiency virus infection. In view of the rarity of these vascular disorders, including pulmonary veno-occlusive disease, it seems unlikely for their association with human immunodeficiency virus infection to occur by chance alone. Further work is needed to elucidate the role that human immunodeficiency virus may have in the pathogenesis of such vascular lesions.
Assuntos
Infecções por HIV/complicações , Pneumopatia Veno-Oclusiva/patologia , Pré-Escolar , Doença Crônica , Humanos , Masculino , Pneumopatia Veno-Oclusiva/etiologiaRESUMO
Congenital cystic adenomatoid malformation and bronchopulmonary sequestration are congenital lung tumors that are classically described as having distinct embryology, pathology, and natural history. The authors treated six patients who had prenatally diagnosed lung masses that displayed clinicopathologic features of both lesion types. At prenatal diagnosis (19 to 30 weeks' gestation), all six lesions were classified sonographically as congenital cystic adenomatoid malformation, and none of the masses appeared to have a systemic arterial blood supply as seen by color flow Doppler study. Two of the six masses showed size regression antenatally. At the time of surgery, all six lesions had a systemic vessel directly from the aorta--five cases were consistent grossly with an intralobular bronchopulmonary sequestration, and one case was consistent with an extralobular bronchopulmonary sequestration. However, all six lesions displayed congenital cystic adenomatoid malformation histology. Hydrops developed in one fetus with a huge mass, and that fetus underwent successful fetal surgical resection (left lower lobectomy) at 22 weeks' gestation with delivery at 35 weeks' gestation. One neonate with a large extralobular bronchopulmonary sequestration was treated with resection and extracorporeal membrane oxygenation (ECMO) but died of pulmonary hypoplasia. Four other patients who had much smaller masses underwent elective lower lobectomy after birth. These findings emphasize the importance of seeking an anomalous blood supply in patients who have congenital lung lesions. These "hybrid" cases suggest a similar embryological origin for congenital cystic adenomatoid malformation and bronchopulmonary sequestration.
Assuntos
Anormalidades Múltiplas , Sequestro Broncopulmonar , Malformação Adenomatoide Cística Congênita do Pulmão , Adulto , Sequestro Broncopulmonar/embriologia , Sequestro Broncopulmonar/patologia , Sequestro Broncopulmonar/cirurgia , Malformação Adenomatoide Cística Congênita do Pulmão/diagnóstico por imagem , Malformação Adenomatoide Cística Congênita do Pulmão/embriologia , Malformação Adenomatoide Cística Congênita do Pulmão/patologia , Malformação Adenomatoide Cística Congênita do Pulmão/cirurgia , Feminino , Doenças Fetais/cirurgia , Humanos , Recém-Nascido , Masculino , Gravidez , Ultrassonografia Pré-NatalRESUMO
We describe a 10 1/2-month-old boy in whom fulminant hepatic failure following chemotherapy for Wilms' tumor developed. He then received an orthotopic liver transplant. An unexpected finding was the accumulation of alpha 1-antitrypsin (AAT) in periportal hepatocytes. A pretransplant serum sample showed a Pi MZ phenotype. The rarity of hepatic failure following treatment for Wilms' tumor raises the possibility of an increased susceptibility to toxic injury in the presence of AAT accumulation. Determination of the frequency of protease inhibitor MZ phenotype in patients who have chemotherapy-related hepatotoxicity could be used to initiate a prospective study aimed at identifying an at-risk population for chemoradiotherapy-related hepatoxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias Renais/tratamento farmacológico , Tumor de Wilms/tratamento farmacológico , Deficiência de alfa 1-Antitripsina , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dactinomicina/administração & dosagem , Dactinomicina/efeitos adversos , Suscetibilidade a Doenças , Hemorragia/induzido quimicamente , Heterozigoto , Humanos , Lactente , Neoplasias Renais/radioterapia , Neoplasias Renais/cirurgia , Hepatopatias/patologia , Transplante de Fígado , Masculino , Necrose , Fenótipo , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Tumor de Wilms/radioterapia , Tumor de Wilms/cirurgia , alfa 1-Antitripsina/genéticaRESUMO
We compared the pathologic and ultrasonographic findings of 31 first trimester spontaneous abortions to determine the benefits of such studies. The ultrasound diagnoses included empty gestational sac (n = 11), intrauterine fetal death (n = 11), abortion in progress or incomplete abortion (n = 8), and live embryo (n = 1). Two subgroups of empty sacs were identified by pathologic examination. Embryonic development appeared to be more advanced in one group as indicated by the presence of embryonic red blood cells (RBC's) in the placental vessels. Although an embryo or fetus was identified more frequently by sonar than by pathologic examination, we were able to diagnose developmental anomalies in small embryos that current ultrasound equipment cannot resolve. Such anomalies were identified even in the presence of fetal heart activity. Pathologic examination was also informative when heavy bleeding obscured the contents of the uterine cavity to sonar and was thus supplementary of a suboptimal ultrasound examination. Placental examination proved to be reliable in assessing gestational age at the time of embryonic/fetal death. There was a good correlation between RBC morphology and sonographic measurement of crown-rump length. First trimester ultrasound and pathologic examination of the embryo and placenta are informative and complement each other.
Assuntos
Aborto Espontâneo/patologia , Aborto Espontâneo/diagnóstico por imagem , Âmnio/diagnóstico por imagem , Âmnio/patologia , Córion/diagnóstico por imagem , Córion/patologia , Feminino , Morte Fetal , Feto/patologia , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Ultrassonografia Pré-NatalRESUMO
We evaluated the possible genetic contribution to hyperinsulinism in a series of patients seen during the past 15 years. Of 26 families, 5 (19%) had more than one child affected (multiplex family). There were no apparent differences between patients in the 5 multiplex and 21 simplex families, clinically, biochemically, or on histologic examination of the pancreatic specimens. The families studied had a total of 63 offspring; the 26 index patients had 37 siblings, 6 of whom were affected. After four patients with hyperinsulinism caused by adenoma were excluded from the study, segregation analysis was carried out to test the data for agreement with results expected if familial and isolated hyperinsulinism represented a single disease with recessive mode of inheritance and a segregation ratio of 0.25. Excellent agreement was found between the observed number of affected siblings (20) and the expected number (19.65), with a segregation ratio of 0.254. The results were consistent with the hypothesis that in most or all cases, hyperinsulinism is inherited as an autosomal recessive disease. There was no evidence of distinct familial and sporadic types.
Assuntos
Genes Recessivos , Hiperinsulinismo/genética , Características da Família , Feminino , Genótipo , Humanos , Hiperinsulinismo/patologia , Hiperinsulinismo/cirurgia , Lactente , Recém-Nascido , Masculino , Pâncreas/patologia , PancreatectomiaRESUMO
Central venulitis (CV), a distinct histologic lesion described in adult liver transplants, can occur with acute portal tract rejection or in isolation (ICV). Possible etiologies include immunosuppressive drug toxicity, acute cellular rejection, viral hepatitis, ischemic injury, and recurrent disease. This study was designed to characterize ICV and to assess its potential etiology in pediatric liver recipients because this population generally does not develop recurrent disease or viral hepatitis. All posttransplantation liver biopsy specimens that were obtained from children who received liver allografts over a 4-year period were reviewed. ICV was identified in 12 of 127 posttransplantation biopsies and in 7 of 45 allograft recipients. Only 4 liver transplantations were performed for potentially recurrent diseases (primary sclerosing cholangitis). ICV first appeared in posttransplantation biopsy specimens significantly later than did portal rejection alone. The finding of CV was not significantly correlated with elevation of Tacrolimus levels, reason for transplantation, donor/recipient cytomegalovirus (CMV) status or blood type, cold ischemic times, or the incidence of outflow obstruction. The responses of CV to therapy were variable and, although the majority of cases resolved, several episodes persisted or recurred. In conclusion, ICV occurs in 16% of pediatric liver allograft recipients and does not appear to be related to recurrent disease, viral hepatitis, drug toxicity, or graft ischemia. CV may be a variant of acute rejection, but longer follow-up is required to determine the most adequate therapy for this entity.