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1.
Histopathology ; 45(3): 283-90, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15330807

RESUMO

AIMS: To determine whether chorioamnionitis has an impact on the extent of apoptosis and proliferation in fetal lungs. Fetuses exposed to chorioamnionitis have an increased risk of aquiring lung tissue damage in utero. METHODS AND RESULTS: Lung tissue sections from 35 stillborn fetuses were used in this study. Chorioamnionitis-exposed fetuses were subdivided depending on whether pneumonia was diagnosed (n = 13) or not (n = 10); 12 unaffected fetuses served as controls. Apoptotic and proliferating cells were determined by in-situ terminal deoxytransferase-mediated dUTP nick end labelling (TUNEL) assay and by anti-Ki67 immunohistochemistry, and quantified. The median apoptotic index in lungs of chorioamnionitis-exposed fetuses increased 2.4-fold compared with chorioamnionitis-negative stillborn controls (P = 0.043) and rose 21.6-fold when chorioamnionitis-exposed fetuses additionally developed pneumonia (P < 0.001). Compared with the proliferation index of the control group (PI = 2.3), the median percentage of proliferating cells in the lungs of chorioamnionitis-exposed fetuses decreased (PI = 1.4) (P = 0.036), but increased 1.8-fold (P = 0.036) in fetal lungs of the chorioamnionitis/pneumonia group. By double labellings combining the TUNEL assay or the Ki67 antigen with cell marker proteins, we identified distal airway epithelial cells as the cell type undergoing apoptosis in chorioamnionitis-exposed fetal lungs, while epithelial, endothelial and smooth muscle cells proliferated. Immunolabellings of cleaved caspases -8 and -9 revealed that apoptosis is mediated via initiator caspase-8. CONCLUSION: Chorioamnionitis induces apoptosis of distal airway epithelial cells via the caspase-8 pathway and interferes with the normal proliferative activity of epithelial, endothelial, and smooth muscle cells in fetal lungs. Thus, apoptosis and proliferation are an important feature of chorioamnionitis-associated lung injury in utero.


Assuntos
Apoptose , Corioamnionite/complicações , Pulmão/patologia , Antígenos CD34/análise , Autopsia , Caspase 3 , Caspase 8 , Caspases/análise , Proliferação de Células , Feminino , Feto , Idade Gestacional , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Queratinas/análise , Antígeno Ki-67/análise , Pulmão/química , Pulmão/embriologia , Pneumopatias/embriologia , Pneumopatias/etiologia , Pneumopatias/metabolismo , Masculino , Gravidez
2.
Eur Respir J ; 23(1): 113-21, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14738242

RESUMO

Apoptosis and proliferation and the effect of exogenous surfactant on these processes were investigated in the lungs of mechanically ventilated/oxygen-treated preterm infants with respiratory distress syndrome and stillborn foetuses. Apoptotic and proliferation indices were determined in lung tissue sections from 27 ventilated/oxygen-treated preterm infants and 29 stillborn foetuses. The effect of exogenous surfactant on apoptosis and proliferation was studied in 16 ventilated preterm infants; 11 untreated infants served as control. Apoptotic and proliferating cells were identified by double labelling combining terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end-labelling or Ki-67 with cell marker proteins. Pathways to cell death were explored by immunolabelling of cleaved caspases-3, -8 and -9. In the lungs of ventilated/oxygen-treated preterm infants, the numbers of apoptotic and proliferating cells increased significantly compared to the respective numbers in the lungs of stillborn foetuses. Apoptosis was detected in alveolar epithelial cells, whereas epithelial, endothelial and smooth muscle cells proliferated. Surfactant treatment reduced apoptosis induced by ventilation/oxygen-treatment; however, the decrease was not significant. Caspases-8 and -9 do not contribute to ventilation-induced apoptosis, whereas caspase-3 is involved. In conclusion, ventilation/oxygen-treatment induces epithelial cell apoptosis and proliferation of epithelial, endothelial and smooth muscle cells in the lungs of preterm infants.


Assuntos
Apoptose/fisiologia , Morte Fetal , Recém-Nascido Prematuro , Pulmão/patologia , Oxigênio/uso terapêutico , Surfactantes Pulmonares/farmacologia , Respiração Artificial , Síndrome do Desconforto Respiratório do Recém-Nascido/patologia , Caspase 3 , Caspase 8 , Caspase 9 , Caspases/fisiologia , Células Endoteliais/patologia , Células Epiteliais/patologia , Morte Fetal/patologia , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Recém-Nascido , Músculo Liso/patologia
3.
Biol Neonate ; 83(3): 166-70, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12660432

RESUMO

The objective of this study was to investigate in a prospective study whether histological chorioamnionitis (ChA) is a risk factor predisposing for intracerebral hemorrhage (ICH), and whether ICH is associated with a systemic fetal inflammation in preterm neonates with a gestational age <32 weeks. 106 neonates were studied; 20 (18.9%) suffered from ICH. ChA occurred significantly more often in neonates with ICH compared to neonates without ICH (70.0 vs. 36.0%, p = 0.006). Neonates with ICH had significantly higher median levels of proinflammatory cytokines (IL-1beta, IL-6 and IL-8) compared to neonates without ICH (p < 0.001 for all comparisons). We conclude that the development of ICH in preterm infants is associated with both ChA and high levels of proinflammatory cytokines at birth.


Assuntos
Hemorragia Cerebral/complicações , Corioamnionite/complicações , Citocinas/sangue , Sangue Fetal , Recém-Nascido Prematuro , Mediadores da Inflamação/sangue , Corioamnionite/epidemiologia , Corioamnionite/patologia , Feminino , Humanos , Incidência , Recém-Nascido , Gravidez
4.
Infection ; 28(3): 137-42, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10879636

RESUMO

BACKGROUND: The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) is essential for replication and maintenance of circular EBV genomes in latently infected B lymphocytes and is the only EBV protein expressed in nearly all cells carrying the virus. EBNA-1 is suggested to be oncogenic in vivo since its expression induces B-cell neoplasia in transgenic mice. PATIENTS, MATERIALS AND METHODS: EBV wild-type isolates from ten malignant tumors and from 15 children with various benign EBV-associated disorders were examined for the presence of EBNA-1 variant strains by PCR and sequencing. RESULTS: One isolate harbored both the B95-8-like and a variant sequence within the C-terminus of the EBNA-1 gene. All other isolates (n = 24) revealed clustered nucleic acid sequence alterations within the EBNA-1 gene, which led to amino acid exchanges at positions 524, 563, 574, 585, 594 and 595. Few isolates exhibited additional amino acid exchanges at positions 564, 571 or 588. CONCLUSIONS: The observed EBNA-1 sequence variation pattern seems not to be restricted to a certain EBV-associated disease or tumor type. The EBNA-1 variant strains reported here may reflect the most prevalent EBV strains in the exposed population. In none of all the cases studied so far did the sequence alteration affect any known functionally crucial amino acids in the core domain of EBNA-1. This suggests that strict conservation of most of the C-terminal portion of EBNA-1 sequence may be essential for survival of EBV in the infected host.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Genes Virais , Herpesvirus Humano 4/genética , Sequência de Bases , Criança , Antígenos Nucleares do Vírus Epstein-Barr/química , Genótipo , Doença de Hodgkin/virologia , Humanos , Linfadenopatia Imunoblástica/virologia , Linfoma não Hodgkin/virologia , Mutação Puntual , Reação em Cadeia da Polimerase , Neoplasias Gástricas/virologia
5.
Prenat Diagn ; 19(5): 483-7, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10360521

RESUMO

Severe type I plasminogen deficiency may cause severe ligneous conjunctivitis, a rare and unusual form of chronic pseudo-membranous conjunctivitis that usually starts in early infancy, but also pseudo-membranous lesions of other mucous membranes in the mouth, nasopharynx, trachea and female genital tract, and in rare cases congenital occlusive hydrocephalus. The index patient, the daughter of a consanguineous marriage, had suffered from severe ligneous conjunctivitis and had died from decompensated congenital hydrocephalus despite numerous shunt revisions. She was found to be homozygous for a non-sense mutation in exon 15 of the plasminogen gene (Trp597->Stop). In her next pregnancy, the mother asked for prenatal diagnosis of the plasminogen deficiency. Chorionic villus biopsy was performed at 12 weeks of gestation. DNA analysis of the plasminogen gene by PCR and single-strand conformation polymorphism (SSCP) revealed that the fetus exhibited an identical heterozygous band pattern as observed in the healthy mother. Therefore, the fetus was heterozygous for the Trp597->Stop mutation in plasminogen exon 15. In addition, the fetus was found to be male by cytogenetic analysis and by multiplex PCR analysis using two polymorphic X-chromosomal markers (DXS424, HPRT). These findings excluded the possibility of contamination by maternal DNA. It was concluded that the fetus was not at risk for ligneous conjunctivitis and its associated complications. After the birth of a healthy boy, plasminogen functional activity was shown to be 38 per cent. DNA analysis confirmed prenatal molecular genetic results.


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos , Conjuntivite/diagnóstico , Doenças Fetais/diagnóstico , Hidrocefalia/diagnóstico , Plasminogênio/deficiência , Diagnóstico Pré-Natal , Adulto , Amostra da Vilosidade Coriônica , Doença Crônica , Conjuntivite/genética , Consanguinidade , Primers do DNA , Feminino , Doenças Fetais/genética , Humanos , Hidrocefalia/genética , Recém-Nascido , Masculino , Linhagem , Plasminogênio/genética , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Gravidez
6.
Blood ; 93(10): 3457-66, 1999 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-10233898

RESUMO

Homozygous type I plasminogen deficiency has been identified as a cause of ligneous conjunctivitis. In this study, 5 additional patients with ligneous conjunctivitis are examined. Three unrelated patients (1 boy, 1 elderly woman, and 1 man) had plasminogen antigen levels of less than 0.4, less than 0.4, and 2.4 mg/dL, respectively, but had plasminogen functional residual activity of 17%, 18%, and 17%, respectively. These subjects were compound-heterozygotes for different missense mutations in the plasminogen gene: Lys19 --> Glu/Arg513 --> His, Lys19 --> Glu/Arg216 --> His, and Lys19 --> Glu/Leu128 --> Pro, respectively. The other 2 patients, a 14-year-old boy and his 19-year-old sister, who both presented with a severe course of the disease, exhibited plasminogen antigen and functional activity levels below the detection limit (<0.4 mg/dL and <5%, respectively). These subjects were compound-heterozygotes for a deletion mutation (del Lys212) and a splice site mutation in intron Q (Ex17 + 1del-g) in the plasminogen gene. These findings show that certain compound-heterozygous mutations in the plasminogen gene may be associated with ligneous conjunctivitis. Our findings also suggest that the severity of clinical symptoms of ligneous conjunctivitis and its associated complications may depend on the amount of plasminogen functional residual activity.


Assuntos
Conjuntivite/genética , Predisposição Genética para Doença , Mutação , Plasminogênio/genética , Adolescente , Adulto , Idoso , Alelos , Substituição de Aminoácidos , Testes de Coagulação Sanguínea , Pré-Escolar , Conjuntivite/sangue , Conjuntivite/patologia , Éxons , Feminino , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Deleção de Sequência
7.
Blood ; 90(3): 958-66, 1997 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-9242524

RESUMO

Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis that usually starts in early infancy. The disease may be associated with pseudomembranous lesions of other mucous membranes in the mouth, nasopharynx, trachea, and female genital tract. We examined two unrelated Turkish girls both suffering from ligneous conjunctivitis and occlusive hydrocephalus. Both children exhibited a severe plasminogen deficiency. Genomic DNA from both patients as well as from clinically healthy family members were screened for mutations in the plasminogen gene by polymerase chain reaction, single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing. In the first girl with ligneous conjunctivitis a homozygous G-->A point mutation was identified in plasminogen exon 7 at position 780 leading to an amino acid exchange (Arg216-->His). Her healthy sister and her healthy parents were heterozygous for this mutation. The second patient revealed a homozygous G-->A point mutation in plasminogen exon 15 at position 1924 which leads to a stop-codon (Trp597-->Stop). The healthy parents were shown to be heterozygous for this mutation. In addition, the father's second allele revealed another mutation in the same codon (Trp597-->Cys) (compound heterozygosity). In conclusion, certain homozygous mutations in the plasminogen gene may cause ligneous conjunctivitis.


Assuntos
Conjuntivite/genética , Plasminogênio/genética , Mutação Puntual , Adolescente , Testes de Coagulação Sanguínea , Conjuntivite/complicações , Conjuntivite/patologia , Consanguinidade , Análise Mutacional de DNA , Síndrome de Dandy-Walker/complicações , Éxons/genética , Evolução Fatal , Feminino , Homozigoto , Humanos , Recém-Nascido , Plasminogênio/deficiência , Polimorfismo Conformacional de Fita Simples , Trombose/complicações , Trombose/genética , Turquia
9.
Am J Med Genet ; 63(1): 318-22, 1996 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-8723128

RESUMO

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disease with a block in differentiation from pre-B to B cells resulting in a selective defect in the humoral immune response. Affected males have very low concentrations of serum immunoglobulins leading predominantly to recurrent bacterial infections beginning at age 6 to 18 months. The gene responsible for XLA was identified recently to encode a cytoplasmatic tyrosine kinase (Bruton's tyrosine kinase, BTK). We have analyzed the BTK gene in a large family in which two brothers presented with the severe phenotype of XLA. Genomic DNA of affected boys and from healthy relatives was amplified by PCR with primers specific for the putative promoter region and for all 19 exons, including flanking intron boundaries, and subsequently screened for mutations using single strand conformation polymorphism (SSCP) analysis. Altered single strand band patterns were found using primers specific for exon 10, 15, and 18. Direct cycle-sequencing of these BTK segments detected two known polymorphisms in intron 14 and in exon 18. Sequencing of exon 10 from two boys with XLA demonstrated a novel point mutation in the SH2 domain of BTK. Direct identification of healthy female carriers in three generations was performed by amplification mutagenesis using PCR with a modified first primer. This method can easily be applied also to prenatal diagnosis.


Assuntos
Agamaglobulinemia/genética , Mutação Puntual , Proteínas Tirosina Quinases/genética , Cromossomo X , Domínios de Homologia de src , Adolescente , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/enzimologia , Agamaglobulinemia/fisiopatologia , Sequência de Aminoácidos , Infecções Bacterianas , Sequência de Bases , Infecções por Campylobacter/etiologia , Campylobacter jejuni , Primers do DNA , Enterite/etiologia , Éxons , Feminino , Triagem de Portadores Genéticos , Marcadores Genéticos , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase
10.
Blood ; 87(4): 1579-85, 1996 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-8608250

RESUMO

In the present study, Epstein-Barr virus (EBV) isolates from 18 malignant tumors (angioimmunoblastic lymphadenopathy [AILD], n = 4; Hodgkin's disease [HD], n = 3; pleomorphic T-cell non-Hodgkin's lymphoma [T-NHL], n = 1; B-cell non-Hodgkin's lymphoma [B-NHL], n = 8; gastric carcinoma, n = 2) as well as from 10 tonsils of EBV-seropositive children and from peripheral blood mononuclear cells of 12 children with uncomplicated infectious mononucleosis (IM) and of a boy with severe chronic active EBV infection were genotyped in the EBV nuclear antigen-2 (EBNA-2) gene. A total of 40 of 41 isolates harbored EBV type 1; in 1 specimen (tonsil), only EBV type 2 was found. Further molecular characterization of EBV type-1 wild-type isolates in the EBNA-2 gene and in the 40-kb distant EBV-encoded small RNAs (EBER) region showed that different groups of stable EBV type-1 variant strains exist in vivo both in benign and malignant lymphatic tissue. Group 1 is composed of EBV type-1 isolates (B-NHL, n = 3; T-NHL, n = 1; HD, n = 1; IM, n = 4) that showed a B95-8-like DNA sequence pattern in both viral genes. Group 2 isolates (HD, n = 1; AILD, n = B-NHL, n = 1; tonsils of EBV-seropositive children, n = 9; IM, n = 20 showed a nucleotide change at position 49095 in the EBNA-2 gene, leading to an amino acid substitution (Pro-->Ser), and EBV type-2 sequences in the EBER region. EBV type-1 isolates that fall into group 3 (AILD, n = 3; HD, n = 1; B-NHL, n = 4; gastric carcinoma, n = 2; IM, n = 6; severe chronic active EBV infection, n = 1) were characterized by typical nucleotide changes and a 3-bp insertion (CTC; extra Leu residue) in the EBNA-2 gene and an EBV type-2-specific sequence pattern in the EBER region. These EBV type-1 variant strains may represent the most prevalent circulating EBV type-1 strains in the exposed population and seem not to be restricted to a certain EBV-associated disease or tumor type. However, analysis of more EBV isolates from benign and malignant lesions must show whether more EBV type-1 substrains exist in vivo.


Assuntos
DNA Viral/genética , Infecções por Herpesviridae/microbiologia , Herpesvirus Humano 4/genética , Linfadenopatia Imunoblástica/microbiologia , Linfoma não Hodgkin/microbiologia , Neoplasias Gástricas/microbiologia , Infecções Tumorais por Vírus/microbiologia , Sequência de Bases , Criança , Primers do DNA/química , Feminino , Genes , Humanos , Mononucleose Infecciosa/microbiologia , Masculino , Dados de Sequência Molecular , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , RNA Viral/genética
11.
J Med Virol ; 48(1): 114-20, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8825720

RESUMO

An EBV type 1 variant strain was detected in two Turkish siblings (boy and girl), who both suffered and died from similar progressive Epstein-Barr virus (EBV)-associated lymphoproliferative disease. Molecular characterisation of this EBV isolate revealed a 51bp-deletion and six nucleotide changes within the Epstein-Barr nuclear antigen 2 (EBNA2). Both isolates contained EBV type 2 sequences in the Epstein-Barr virus-encoded small RNAs (EBER), which are 40 kb proximal to EBNA2. Sequencing of the EBV isolates in a region of Epstein-Barr nuclear antigen 3 (EBNA3a), which is 40 kb distal to EBNA2, revealed the normal EBV type 1 sequence of laboratory strain B95-8. This EBV isolate may represent a distinct wild type EBV strain with altered biological properties. It is suggested that this EBNA2-variant strain may be responsible at least in part for the severe clinical course in both affected children.


Assuntos
DNA Viral/genética , Antígenos Nucleares do Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Transtornos Linfoproliferativos/virologia , Sequência de Aminoácidos , Sequência de Bases , Medula Óssea/patologia , Medula Óssea/virologia , Linhagem Celular Transformada , Evolução Fatal , Feminino , Variação Genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Linfonodos/patologia , Linfonodos/virologia , Transtornos Linfoproliferativos/fisiopatologia , Masculino , Dados de Sequência Molecular , Mutação
12.
Klin Padiatr ; 207(5): 271-6, 1995.
Artigo em Alemão | MEDLINE | ID: mdl-7500602

RESUMO

X-linked lymphoproliferative disease (XLP) is a rare worldwide occurring inherited immunodeficiency which is triggered by Epstein-Barr virus infection. Clinical phenotypes in 21 affected males from 5 German families with XLP ranged from severe and fatal infectious mononucleosis (57%) to acquired hypogammaglobulinaemia (28%), malignant lymphoma (28%), aplastic anaemia (19%) and hypergammaglobulinaemia M (19%). Molecular genetic studies with various polymorphic X-chromosomal DNA markers in 14 XLP families mapped the XLP gene locus to Xq25-q26. Haplotype analysis enables detection of XLP-positive and XLP-negative males already before EBV-infection as well as diagnosis of healthy female carriers within XLP families.


Assuntos
Genes Recessivos/genética , Ligação Genética/genética , Transtornos Linfoproliferativos/genética , Aberrações dos Cromossomos Sexuais/genética , Cromossomo X , Criança , Pré-Escolar , Mapeamento Cromossômico , Sondas de DNA , Feminino , Triagem de Portadores Genéticos , Marcadores Genéticos/genética , Haplótipos , Herpesvirus Humano 4/genética , Humanos , Mononucleose Infecciosa/genética , Masculino , Linhagem , Fenótipo
14.
Eur J Pediatr ; 153(6): 432-7, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7916289

RESUMO

Three families with X-linked lymphoproliferative disease were studied. Affected males clinically presented with severe or fatal infectious mononucleosis, acquired hypogammaglobulinaemia, hypergammaglobulinaemia M, and malignant lymphoma including Hodgkin disease. Haplotype analysis using various DNA markers from Xq25-q27 allowed the prediction of the carrier status in females and identification of the XLP status in asymptomatic males.


Assuntos
Ligação Genética , Haplótipos , Transtornos Linfoproliferativos/genética , Cromossomo X , Sequência de Bases , Feminino , Heterozigoto , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição
15.
Monatsschr Kinderheilkd ; 141(5): 401-4, 1993 May.
Artigo em Alemão | MEDLINE | ID: mdl-8392141

RESUMO

A male infant infected in utero with EBV clinically presented after birth with dystrophy, generalized hypotonia, hepatosplenomegaly, diffuse petechiae and hematomas, metaphysis of the long bones, anemia, hyperbilirubinemia and elevated serum transaminases, lymphocytosis and thrombocytopenia. Malformations were absent. Specific serologic studies suggested congenital EBV infection in the newborn infant and primary EBV infection in the mother. Other known congenital infections could be excluded.


Assuntos
Anticorpos Antivirais/análise , Herpesvirus Humano 4/imunologia , Mononucleose Infecciosa/congênito , Complicações Infecciosas na Gravidez/imunologia , Adulto , Feminino , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/imunologia , Seguimentos , Humanos , Lactente , Recém-Nascido , Mononucleose Infecciosa/diagnóstico , Mononucleose Infecciosa/imunologia , Masculino , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico
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