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1.
Hernia ; 27(3): 583-592, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36574083

RESUMEN

PURPOSE: While many factors have been correlated with lesser outcomes in abdominal wall reconstruction (AWR), the impact of surgeon experience has yet to be elucidated. We sought to evaluate the effect of cumulative surgeon experience on long-term complex AWR outcomes. METHODS: We conducted a comprehensive review of all consecutive patients who underwent AWR using biologic mesh for the repair of ventral hernias or tumor resection defects from March 2005 to June 2019. The primary outcome measure was hernia recurrence (HR). Secondary outcomes were surgical site occurrences (SSOs) and surgical site infections (SSIs). Patients were a priori categorized into the following groups according to the cumulative number of hernia repairs performed by their surgeons: low (< 50), moderate experience (50-100), and high (> 100) experience. RESULTS: We identified 60 surgeons and 650 consecutive patients (62% women) who met our inclusion criteria. In adjusted models, AWR performed by surgeons with high experience was associated with a fourfold lower risk of HR (hazard ratio, 0.28; 95% confidence interval, 0.08 to 0.87), but the odds of surgical site occurrences (odds ratio, 0.72, 95% confidence interval, 0.34 to 1.52) and surgical site infections (odds ratio, 0.89, 95% confidence interval, 0.26 to 2.86) did not differ significantly in the high-experience group. CONCLUSIONS: High surgical experience, defined as > 100 cumulative hernia repairs, is predictive for markedly lower HR rates in complex AWR. These findings have potential implications for preoperative risk assessment, patient-centered surgeon selection, regulatory oversight, specific referral patterns, designations of centers of excellence, and individual provider or trainee quality improvement.


Asunto(s)
Pared Abdominal , Hernia Ventral , Cirujanos , Humanos , Femenino , Masculino , Pared Abdominal/cirugía , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/etiología , Infección de la Herida Quirúrgica/cirugía , Herniorrafia/efectos adversos , Estudios Retrospectivos , Hernia Ventral/cirugía , Mallas Quirúrgicas , Recurrencia , Resultado del Tratamiento
3.
Proc Natl Acad Sci U S A ; 98(12): 6692-7, 2001 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-11381139

RESUMEN

The ubiquitously expressed basic helix-loop-helix (bHLH)-PAS protein ARNT (arylhydrocarbon receptor nuclear transporter) forms transcriptionally active heterodimers with a variety of other bHLH-PAS proteins, including HIF-1alpha (hypoxia-inducible factor-1alpha) and AHR (arylhydrocarbon receptor). These complexes regulate gene expression in response to hypoxia and xenobiotics, respectively, and mutation of the murine Arnt locus results in embryonic death by day 10.5 associated with placental, vascular, and hematopoietic defects. The closely related protein ARNT2 is highly expressed in the central nervous system and kidney and also forms complexes with HIF-1alpha and AHR. To assess unique roles for ARNT2 in development, and reveal potential functional overlap with ARNT, we generated a targeted null mutation of the murine Arnt2 locus. Arnt2(-/-) embryos die perinatally and exhibit impaired hypothalamic development, phenotypes previously observed for a targeted mutation in the murine bHLH-PAS gene Sim1 (Single-minded 1), and consistent with the recent proposal that ARNT2 and SIM1 form an essential heterodimer in vivo [Michaud, J. L., DeRossi, C., May, N. R., Holdener, B. C. & Fan, C. (2000) Mech. Dev. 90, 253-261]. In addition, cultured Arnt2(-/-) neurons display decreased hypoxic induction of HIF-1 target genes, demonstrating formally that ARNT2/HIF-1alpha complexes regulate oxygen-responsive genes. Finally, a strong genetic interaction between Arnt and Arnt2 mutations was observed, indicating that either gene can fulfill essential functions in a dose-dependent manner before embryonic day 8.5. These results demonstrate that Arnt and Arnt2 have both unique and overlapping essential functions in embryonic development.


Asunto(s)
Receptores de Hidrocarburo de Aril , Factores de Transcripción/genética , Alelos , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Proteínas de Unión al ADN/química , Dimerización , Desarrollo Embrionario y Fetal , Hipoxia/metabolismo , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ratones , Mutación , Proteínas Nucleares/química , Factores de Transcripción/química , Factores de Transcripción/fisiología
4.
Genes Dev ; 14(24): 3191-203, 2000 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-11124810

RESUMEN

Placental development is profoundly influenced by oxygen (O(2)) tension. Human cytotrophoblasts proliferate in vitro under low O(2) conditions but differentiate at higher O(2) levels, mimicking the developmental transition they undergo as they invade the placental bed to establish the maternal-fetal circulation in vivo. Hypoxia-inducible factor-1 (HIF-1), consisting of HIF-1alpha and ARNT subunits, activates many genes involved in the cellular and organismal response to O(2) deprivation. Analysis of Arnt(-/-) placentas reveals an aberrant cellular architecture due to altered cell fate determination of Arnt(-/-) trophoblasts. Specifically, Arnt(-/-) placentas show greatly reduced labyrinthine and spongiotrophoblast layers, and increased numbers of giant cells. We further show that hypoxia promotes the in vitro differentiation of trophoblast stem cells into spongiotrophoblasts as opposed to giant cells. Our results clearly establish that O(2) levels regulate cell fate determination in vivo and that HIF is essential for mammalian placentation. The unique placental phenotype of Arnt(-/-) animals also provides an important tool for studying the disease of preeclampsia. Interestingly, aggregation of Arnt(-/-) embryonic stem (ES) cells with tetraploid wild-type embryos rescues their placental defects; however, these embryos still die from yolk sac vascular and cardiac defects.


Asunto(s)
Hipoxia de la Célula/fisiología , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Placenta/citología , Receptores de Hidrocarburo de Aril , Factores de Transcripción/genética , Trofoblastos/citología , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo , División Celular/genética , Células Cultivadas , Proteínas de Unión al ADN/genética , Endotelio Vascular/patología , Femenino , Corazón/embriología , Corazón/crecimiento & desarrollo , Cardiopatías Congénitas/genética , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ratones , Ratones Transgénicos , Proteínas Nucleares/genética , Placenta/irrigación sanguínea , Placenta/fisiología , Poliploidía , Embarazo , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta3 , Trofoblastos/fisiología , Saco Vitelino/anomalías , Saco Vitelino/crecimiento & desarrollo
6.
Mol Cell ; 6(6): 1389-99, 2000 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11163212

RESUMEN

Proapoptotic Bcl-2 family members have been proposed to play a central role in regulating apoptosis. However, mice lacking bax display limited phenotypic abnormalities. As presented here, bak(-/-) mice were found to be developmentally normal and reproductively fit and failed to develop any age-related disorders. However, when Bak-deficient mice were mated to Bax-deficient mice to create mice lacking both genes, the majority of bax(-/-)bak(-/-) animals died perinatally with fewer than 10% surviving into adulthood. bax(-/-)bak(-/-) mice displayed multiple developmental defects, including persistence of interdigital webs, an imperforate vaginal canal, and accumulation of excess cells within both the central nervous and hematopoietic systems. Thus, Bax and Bak have overlapping roles in the regulation of apoptosis during mammalian development and tissue homeostasis.


Asunto(s)
Anomalías Múltiples/genética , Apoptosis , Eliminación de Gen , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Encéfalo/anomalías , Células Cultivadas , Cruzamientos Genéticos , Desarrollo Embrionario y Fetal/genética , Etopósido/farmacología , Femenino , Marcación de Gen , Genes Esenciales/genética , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Histocitoquímica , Riñón/anomalías , Riñón/patología , Tejido Linfoide/anomalías , Tejido Linfoide/patología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Fenotipo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Bazo/anomalías , Bazo/patología , Timo/anomalías , Timo/patología , Proteína Destructora del Antagonista Homólogo bcl-2 , Proteína X Asociada a bcl-2 , Receptor fas/fisiología
7.
Genes Dev ; 13(19): 2478-83, 1999 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-10521392

RESUMEN

Although most cells undergo growth arrest during hypoxia, endothelial cells and placental cytotrophoblasts proliferate in response to low O(2). We demonstrate that proliferation of embryonic multilineage hematopoietic progenitors is also regulated by a hypoxia-mediated signaling pathway. This pathway requires HIF-1 (HIF-1alpha/ARNT heterodimers) because Arnt(-/-) embryoid bodies fail to exhibit hypoxia-mediated progenitor proliferation. Furthermore, Arnt(-/-) embryos exhibit decreased numbers of yolk sac hematopoietic progenitors. This defect is cell extrinsic, is accompanied by a decrease in ARNT-dependent VEGF expression, and is rescued by exogenous VEGF. Therefore, "physiologic hypoxia" encountered by embryos is essential for the proliferation or survival of hematopoietic precursors during development.


Asunto(s)
Hematopoyesis/fisiología , Receptores de Hidrocarburo de Aril/fisiología , Factores de Transcripción/fisiología , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo , Diferenciación Celular , Hipoxia de la Célula , Linaje de la Célula , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Factores de Crecimiento Endotelial/genética , Eritropoyetina/genética , Femenino , Células Madre Hematopoyéticas/citología , Humanos , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Linfocinas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/metabolismo , Células Madre , Factores de Transcripción/genética , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
8.
Protein Sci ; 3(4): 549-56, 1994 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8003973

RESUMEN

We examine the role of the conformational restriction imposed by constrained ends of a protein loop on the determination of a strained loop conformation. The Lys 116-Pro 117 peptide bond of staphylococcal nuclease A exists in equilibrium between the cis and trans isomers. The folded protein favors the strained cis isomer with an occupancy of 90%. This peptide bond is contained in a solvent-exposed, flexible loop of residues 112-117 whose ends are anchored by Val 111 and Asn 118. Asn 118 is constrained by 2 side-chain hydrogen bonds. We investigate the importance of this constraint by replacing Asn 118 with aspartate, alanine, and glycine. We found that removing 1 or more of the hydrogen bonds observed in Asn 118 stabilizes the trans configuration over the cis configuration. By protonating the Asp 118 side chain of N118D through decreased pH, the hydrogen bonding character of Asp 118 approached that of Asn 118 in nuclease A, and the cis configuration was stabilized relative to the trans configuration. These data suggest that the rigid anchoring of the loop end is important in establishing the strained cis conformation. The segment of residues 112-117 in nuclease A provides a promising model system for study of the basic principles that determine polypeptide conformations. Such studies could be useful in the rational design or redesign of protein molecules.


Asunto(s)
Nucleasa Microcócica/química , Histidina/química , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pliegue de Proteína , Termodinámica
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