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1.
N Engl J Med ; 383(12): 1107-1116, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32786180

RESUMEN

BACKGROUND: In the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to chromosomal abnormalities. However, the causal nature of single-nucleotide variants and small insertions and deletions in exomes has been understudied. METHODS: We generated exome sequencing data for 246 stillborn cases and followed established guidelines to identify causal variants in disease-associated genes. These genes included those that have been associated with stillbirth and strong candidate genes. We also evaluated the contribution of 18,653 genes in case-control analyses stratified according to the degree of depletion of functional variation (described here as "intolerance" to variation). RESULTS: We identified molecular diagnoses in 15 of 246 cases of stillbirth (6.1%) involving seven genes that have been implicated in stillbirth and six disease genes that are good candidates for phenotypic expansion. Among the cases we evaluated, we also found an enrichment of loss-of-function variants in genes that are intolerant to such variation in the human population (odds ratio, 2.15; 95% confidence interval [CI], 1.46 to 3.06). Loss-of-function variants in intolerant genes were concentrated in genes that have not been associated with human disease (odds ratio, 2.22; 95% CI, 1.41 to 3.34), findings that differ from those in two postnatal clinical populations that were also evaluated in this study. CONCLUSIONS: Our findings establish the diagnostic utility of clinical exome sequencing to evaluate the role of small genomic changes in stillbirth. The strength of the novel risk signal (as generated through the stratified analysis) was similar to that in known disease genes, which indicates that the genetic cause of stillbirth remains largely unknown. (Funded by the Institute for Genomic Medicine.).


Asunto(s)
Variación Genética , Mutación , Mortinato/genética , Femenino , Mutación del Sistema de Lectura , Humanos , Mutación con Pérdida de Función , Mutación Missense , Embarazo , Secuenciación del Exoma
2.
Ann Neurol ; 2022 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-36534060

RESUMEN

OBJECTIVE: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. METHODS: We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. RESULTS: Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. INTERPRETATION: Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.

3.
Am J Med Genet A ; 188(1): 138-146, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34569149

RESUMEN

Large international consortia examining the genomic architecture of the epilepsies focus on large diagnostic subgroupings such as "all focal epilepsy" and "all genetic generalized epilepsy". In addition, phenotypic data are generally entered into these large discovery databases in a unidirectional manner at one point in time only. However, there are many smaller phenotypic subgroupings in epilepsy, many of which may have unique genomic risk factors. Such a subgrouping or "microphenotype" may be defined as an uncommon or rare phenotype that is well recognized by epileptologists and the epilepsy community, and which may or may not be formally recognized within the International League Against Epilepsy classification system. Here we examine the genetic structure of a number of such microphenotypes and report in particular on two interesting clinical phenotypes, Jeavons syndrome and pediatric status epilepticus. Although no single gene reached exome-wide statistical significance to be associated with any of the diagnostic categories, we observe enrichment of rare damaging variants in established epilepsy genes among Landau-Kleffner patients (GRIN2A) and pediatric status epilepticus patients (MECP2, SCN1A, SCN2A, SCN8A).


Asunto(s)
Epilepsia Generalizada , Epilepsia , Niño , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Exoma , Genómica , Humanos , Fenotipo
4.
Epilepsia ; 63(3): 723-735, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35032048

RESUMEN

OBJECTIVE: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. METHODS: We performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113 genes representing the GABAergic pathway). RESULTS: GABRG2 was associated with GGE (p = 1.8 × 10-5 ), approaching study-wide significance in familial GGE (p = 3.0 × 10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9-7.8, false discovery rate [FDR]-adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3-6.7, FDR-adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3-2.5, FDR-adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9-1.9, FDR-adjusted p = .19). SIGNIFICANCE: URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.


Asunto(s)
Epilepsia Generalizada , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , Epilepsia Generalizada/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Receptores de GABA-A/genética , Secuenciación del Exoma , Ácido gamma-Aminobutírico
5.
N Engl J Med ; 383(27): 2687-2688, 2020 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-33382938
6.
Nat Commun ; 15(1): 2220, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38472221

RESUMEN

Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy.


Asunto(s)
Ácidos Nucleicos Libres de Células , Humanos , Fragmentación del ADN , Transcriptoma , Biología , Biomarcadores de Tumor/genética
7.
J Perinatol ; 42(5): 677-682, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34230605

RESUMEN

Due to the changing complex healthcare environment, educational innovation is essential to meet the needs of current and future neonatal-perinatal medicine (NPM) leaders. Greater clinical demands, decreased academic funding, and expanded graduate medical education program requirements have negatively impacted time for teaching and educational scholarship potentially limiting innovation in the field. By focusing on adult learning principles, embracing technology, and promoting collaboration, today's educators are preparing the next generation of neonatologists. Current innovations include regionalizing simulation boot camps, leveraging virtual learning to increase accessibility, developing niche training opportunities, and incorporating population health principles within existing quality initiatives. Areas in need of additional innovation include faculty and fellow development for teaching skills, expansion of educational networks, and dissemination and financial support of educational scholarship. These efforts and future innovations will require medical institutions and national NPM organizations to further invest in the medical educator as part of their missions.


Asunto(s)
Curriculum , Becas , Adulto , Educación de Postgrado en Medicina , Femenino , Humanos , Recién Nacido , Embarazo
8.
NPJ Genom Med ; 7(1): 55, 2022 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-36100603

RESUMEN

The early detection of tissue and organ damage associated with autoimmune diseases (AID) has been identified as key to improve long-term survival, but non-invasive biomarkers are lacking. Elevated cell-free DNA (cfDNA) levels have been observed in AID and inflammatory bowel disease (IBD), prompting interest to use cfDNA as a potential non-invasive diagnostic and prognostic biomarker. Despite these known disease-related changes in concentration, it remains impossible to identify AID and IBD patients through cfDNA analysis alone. By using unsupervised clustering on large sets of shallow whole-genome sequencing (sWGS) cfDNA data, we uncover AID- and IBD-specific genome-wide patterns in plasma cfDNA in both the obstetric and general AID and IBD populations. We demonstrate that pregnant women with AID and IBD have higher odds of receiving inconclusive non-invasive prenatal screening (NIPS) results. Supervised learning of the genome-wide patterns allows AID prediction with 50% sensitivity at 95% specificity. Importantly, the method has the potential to identify pregnant women with AID during routine NIPS. Since AID pregnancies have an increased risk of severe complications, early recognition or detection of new-onset AID can redirect pregnancy management and limit potential adverse events. This method opens up new avenues for screening, diagnosis and monitoring of AID and IBD.

9.
J Am Assoc Nurse Pract ; 34(2): 292-297, 2021 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-34115717

RESUMEN

BACKGROUND: Hepatitis C virus (HCV) infections have increased significantly in the United States recently, having tripled by 2014. Seventy-five percent of those with HCV are aging baby boomers, which places increased pressure on the medical system to provide treatment. There are not enough specialists available to treat everyone infected with HCV. PURPOSE: The aim of this research was to determine whether treatment of hepatitis C with new direct-acting antivirals in primary care settings resulted in equivalent cure rates when compared with those patients treated by specialists. METHODOLOGY: A retrospective cohort design was used. Participants were those treated for hepatitis C in specialty care at large public hospitals by gastroenterologists and/or hepatologists and those treated in two primary care community health centers in Seattle. Multivariate logistic regression was used to determine differences of sustained virologic response between those treated in primary care and those treated in specialty care. Treatment failure and those lost to follow-up were combined into one category. RESULTS: Failure rates were only 4% in primary care and 1.1% in specialty care. After adjustment, patients treated in primary care were statistically significantly less likely to have failure/lost to follow-up than those treated in specialty care. Hepatitis C treatment can be successfully provided in primary care with equivalent treatment outcomes. IMPLICATIONS FOR PRACTICE: Primary care advanced practice nurses are in a good position to identify and treat hepatitis C. In addition, as patients are typically more engaged with their primary care provider, follow-up rates may be better versus referring these patients to a specialty provider.


Asunto(s)
Hepatitis C Crónica , Hepatitis C , Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Humanos , Atención Primaria de Salud , Estudios Retrospectivos , Resultado del Tratamiento , Estados Unidos
10.
J Hum Lact ; 37(1): 62-70, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32735504

RESUMEN

BACKGROUND: The use of donor human milk is rising. Maternal awareness of donor human milk use, milk donation, and milk banks has not been well described in the United States. RESEARCH AIMS: To explore maternal experience, knowledge, and attitudes regarding donor human milk use and milk donation. We also assessed counseling by medical providers about donor human milk use and donation. METHODS: A cross-sectional prospective survey design was used in this study. We anonymously surveyed mothers (N = 73) attending the 1 to 2-week well newborn appointment. Analyses were completed using one-way ANOVA and logistic regression. RESULTS: Participants' infants primarily received their own mother's milk (87%, n = 61). No infants received donor human milk, but 4% (n = 3) of participants donated milk. The majority of participants had positive responses to attitudinal statements about donor milk. When presented with a hypothetical scenario, participants chose formula (89%, n = 59) over donor human milk (11%, n = 7) for their infant. Moreover, if donor human milk was the only option available, they chose donor human milk from a relative or friend (60%, n = 40) over a milk bank (40%, n = 26). Medical providers had discussed donor human milk use or donation with 4% (n = 3) of participants. CONCLUSIONS: The majority of participants previously had minimal experience using donor human milk and limited knowledge regarding donor human milk and milk banks. According to participants, medical providers did not routinely discuss milk donation and the role of donor human milk with families.


Asunto(s)
Bancos de Leche Humana , Lactancia Materna , Estudios Transversales , Femenino , Humanos , Lactante , Recién Nacido , Leche Humana , Madres , Estudios Prospectivos
11.
MedEdPORTAL ; 17: 11097, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33598540

RESUMEN

Introduction: Neonatal-perinatal medicine (NPM) providers actively manage medical transports. However, there is wide variation in transport education among fellowship programs. Using the flipped classroom methodology, we developed a video and case-based transport education curriculum. Methods: A national needs assessment identified safety, communication skills, and physiology as the most important aspects of transport management. Three 10-minute video modules and two 20-minute case-based discussions were developed to address this content. Using the flipped classroom format, seven NPM fellows from all three postgraduate years of training took part in the curriculum by individually viewing each video followed by participation in group case-based discussions. Cognitive and affective outcomes were assessed using a knowledge and attitude pretest, individual video module posttests, and a postcurriculum follow-up survey. Results: NPM fellows showed significant improvements in transport knowledge and reported increased confidence in their ability to perform important transport roles. Case discussions were adaptable to learners who had different levels of training and had variable transport experience. Case discussions were successfully executed both in person and by video telecommunications during the 2020 COVID-19 pandemic. Discussion: This transport curriculum addressed a national education gap in NPM fellowship training. Using the flipped classroom methodology, cognitive and affective objectives were achieved by improving knowledge and confidence in transport skills among NPM learners. The video and case-based formats were easily implemented, applicable to multiple types of learners, and adaptable to different environments.


Asunto(s)
COVID-19 , Instrucción por Computador , Curriculum , Educación de Postgrado en Medicina , Pediatría/educación , Aprendizaje Basado en Problemas , SARS-CoV-2 , Apoyo a la Formación Profesional , Evaluación Educacional , Humanos , Recién Nacido , Michigan , Pandemias , Grabación en Video
12.
Fertil Steril ; 114(1): 33-43, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32622411

RESUMEN

OBJECTIVE: To identify cell types in the male and female reproductive systems at risk for SARS-CoV-2 infection because of the expression of host genes and proteins used by the virus for cell entry. DESIGN: Descriptive analysis of transcriptomic and proteomic data. SETTING: Academic research department and clinical diagnostic laboratory. PATIENT(S): Not applicable (focus was on previously generated gene and protein expression data). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Identification of cell types coexpressing the key angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) genes and proteins as well as other candidates potentially involved in SARS-CoV-2 cell entry. RESULT(S): On the basis of single-cell RNA sequencing data, coexpression of ACE2 and TMPRSS2 was not detected in testicular cells, including sperm. A subpopulation of oocytes in nonhuman primate ovarian tissue was found to express ACE2 and TMPRSS2, but coexpression was not observed in ovarian somatic cells. RNA expression of TMPRSS2 in 18 samples of human cumulus cells was shown to be low or absent. There was general agreement between publicly available bulk RNA and protein datasets in terms of ACE2 and TMPRSS2 expression patterns in testis, ovary, endometrial, and placental cells. CONCLUSION(S): These analyses suggest that SARS-CoV-2 infection is unlikely to have long-term effects on male and female reproductive function. Although the results cannot be considered definitive, they imply that procedures in which oocytes are collected and fertilized in vitro are associated with very little risk of viral transmission from gametes to embryos and may indeed have the potential to minimize exposure of susceptible reproductive cell types to infection in comparison with natural conception.


Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/metabolismo , Fertilidad/fisiología , Regulación Viral de la Expresión Génica/fisiología , Neumonía Viral/metabolismo , Reproducción/fisiología , Internalización del Virus , Adolescente , Adulto , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/genética , COVID-19 , Línea Celular , Infecciones por Coronavirus/genética , Femenino , Humanos , Macaca fascicularis , Masculino , Ovario/citología , Ovario/metabolismo , Ovario/virología , Pandemias , Peptidil-Dipeptidasa A/biosíntesis , Peptidil-Dipeptidasa A/genética , Neumonía Viral/genética , Embarazo , Proteómica/métodos , SARS-CoV-2 , Serina Endopeptidasas/biosíntesis , Serina Endopeptidasas/genética , Testículo/citología , Testículo/metabolismo , Testículo/virología , Transcriptoma/fisiología , Adulto Joven
13.
Breastfeed Med ; 15(2): 79-83, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31855456

RESUMEN

Background: Postpartum mothers express and store breast milk using a hospital-grade pump and manufacturer-specific kit (flanges, bottles, tubing, valves, and membranes). After hospital discharge, mothers may attempt to interchange kits from different manufacturers. The objective of this study is to determine whether pump performance is affected by the use of a different manufacturer's kit. Materials and Methods: Suction pressure was tested using kits and six pumps from three manufacturers (Ameda, Medela, and Spectra). Pump settings (speed and vacuum strength) simulated maximum, minimum, and commonly used median settings. Suction pressure (mmHg) was measured using an analog gauge and repeated six times for each pump-kit combination. Measurements were compared using repeated measures analysis of covariance (ANCOVA) to determine whether kit was an independent predictor of suction pressure. Results: The kit type was a significant independent predictor (p < 0.05) of suction pressure for all at medium vacuum strength and many at maximum and minimum vacuum strengths. Upon further analysis interchanging kits resulted in both significantly increased and decreased suction pressures compared to the manufacturer-specific kit. Conclusion: Breast pump kits generate variable suction pressures when interchanged between pumps from different manufacturers. Interchanging combinations of kits and breast pumps could potentially lead to low milk expression due to ineffective suction pressure or increased discomfort from excessive pressure. The results of this study emphasize the importance of maternal education regarding the use of manufacturer-specific kits and breast pumps.


Asunto(s)
Extracción de Leche Materna/instrumentación , Diseño de Equipo/normas , Succión/normas , Femenino , Humanos
14.
JPEN J Parenter Enteral Nutr ; 44(5): 904-911, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31599047

RESUMEN

BACKGROUND: In neonatal chylothorax, thoracic lymphatic drainage is ineffective. The resultant effusions often require drainage, leading to a loss of immune components. Affected infants can be managed with formula or defatted human milk feedings low in long-chain triglycerides to decrease lymph production. We hypothesized that there is no significant difference in the immunological profile or antibacterial effect of full-fat and defatted human milk. METHODS: Milk from lactating mothers was divided into 1 aliquot that was defatted via centrifugation with the full-fat aliquot as control. Macronutrient content was analyzed with mid-infrared spectroscopy. Flow cytometry was used to measure immune cell populations. Lactoferrin, lysozyme, immunoglobulin (Ig)A, and IgG values were determined using enzyme-linked immunosorbent assay. The antibacterial properties were determined by inoculating paired full-fat and defatted milk samples with Escherichia coli or Streptococcus pneumoniae bacteria and performing colony counts. RESULTS: Compared with full-fat milk, defatted milk demonstrated decreased total energy and fat and increased carbohydrate concentrations. Defatted milk demonstrated a significant decrease in all immune cell populations. There was no difference in IgA, IgG, lysozyme, or lactoferrin concentrations. Both aliquots demonstrated equivalent growth inhibition of E. coli and S. pneumoniae. CONCLUSIONS: Unexpectedly, defatted human milk contained significantly less leukocytes than full-fat milk. IgA, IgG, lysozyme, and lactoferrin concentrations were preserved. The ability of defatted milk to inhibit bacterial growth was unaffected, suggesting that the antibacterial benefits of human milk remain after the defatting process. Further investigation regarding the clinical effect of leukocyte loss in defatted milk is warranted.


Asunto(s)
Grasas de la Dieta , Leche Humana/inmunología , Animales , Escherichia coli , Femenino , Humanos , Inmunoglobulina A , Lactante , Lactancia , Leche Humana/metabolismo , Muramidasa
15.
Int Breastfeed J ; 15(1): 8, 2020 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-32066477

RESUMEN

BACKGROUND: A key reason for premature cessation of breastfeeding is inadequate support from healthcare providers. Most physicians and nurses do not feel confident in their ability to support families with breastfeeding initiation or maintenance. Increasing health professional confidence in clinical lactation skills is key to improving maternal and child health outcomes. High-fidelity (realistic) simulators encourage learner engagement, resulting in increased clinical skills competency, confidence, and transfer to patient care. Lactation educators teach with low-fidelity cloth and single breast models. There are no high-fidelity breast simulators for health professional education in clinical lactation. DEVELOPMENT AND EVALUATION OF A HIGH-FIDELITY LACTATION SIMULATION MODEL: In this commentary we describe the development of a high-fidelity Lactation Simulation Model (LSM) and how physician residents, nurse-midwifery students, and clinical lactation experts provided feedback on LSM prototypes. LIMITATIONS: The user-testing described in this commentary does not represent comprehensive validation of the LSM due to small sample sizes and the significant conflict of interest. CONCLUSION: For breastfeeding rates to improve, mothers need support from their nurses, midwives, pediatricians, obstetricians and gynecologists, and all healthcare staff who interact with pregnant and lactating women. Clinical education with high-fidelity breastfeeding simulators could be the ideal learning modality for trainees and hospital staff to build confidence in clinical lactation skills. The ability of a high-fidelity breastfeeding simulator to increase a learner's lactation knowledge and psychomotor skills acquisition, retention, and transfer to patient care still needs to be tested.


Asunto(s)
Lactancia Materna , Competencia Clínica , Personal de Salud/educación , Capacitación en Servicio , Modelos Anatómicos , Femenino , Humanos , Recién Nacido , Embarazo
16.
Artículo en Inglés | MEDLINE | ID: mdl-29351195

RESUMEN

Human beings think in metaphor and reason through analogy. The metaphors through which we think influence how we understand and feel about social issues as well as the actions that we see as appropriate and important. Metaphors can be used to increase understanding of how issues work and increase the salience of a given issue, build support for programs and policies necessary to address the issue, and instigate demand for change and civic action. In this paper, we use a mixed methods research design, including brief qualitative interviews, experimental surveys, and focus groups, to test the ability of different metaphors to influence public understanding of the social determinants of child abuse and neglect in the UK. We find one metaphor in particular that improves people's understanding of the social causes of child maltreatment and increases support for structural solutions. This metaphor can be used to build support for preventative public health solutions.


Asunto(s)
Maltrato a los Niños , Comunicación , Metáfora , Opinión Pública , Investigación , Niño , Cultura , Grupos Focales , Humanos , Política Pública , Conducta Social , Encuestas y Cuestionarios
18.
Am J Physiol Lung Cell Mol Physiol ; 290(2): L298-306, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16155089

RESUMEN

Nitric oxide (NO) is a vasodilator produced from L-arginine (L-Arg) by NO synthase (NOS). Gene therapy for hypertensive disorders has been proposed using the inducible isoform of NOS (iNOS). L-Arg also can be metabolized to urea and L-ornithine (L-Orn) by arginase, and L-Orn can be metabolized to proline and/or polyamines, which are vital for cellular proliferation. To determine the effect of iNOS gene transfer on arginase, we transfected bovine pulmonary arterial endothelial cells (bPAEC) with an adenoviral vector containing the gene for iNOS (AdiNOS). As expected, NO production in AdiNOS bPAEC was substantially greater than in control bPAEC. Although urea production was significantly less in the AdiNOS bPAEC than in the control bPAEC, despite similar levels of arginase I protein, AdiNOS transfection of bPAEC had no effect on the uptake of L-Arg. Inhibiting NO production with Nomega-nitro-L-arginine methyl ester increased urea production, and inhibiting urea production with L-valine increased nitrite production, in AdiNOS bPAEC. The addition of L-Arg to the medium increased urea production by AdiNOS bPAEC in a concentration-dependent manner. Thus, in these iNOS-transfected bPAEC, the transfected iNOS and native arginase compete for a common intracellular pool of L-Arg. This competition for substrate resulted in impaired proliferation in the AdiNOS-transfected bPAEC. These findings suggest that the use of iNOS gene therapy for pulmonary hypertensive disorders may not only be beneficial through NO-mediated pulmonary vasodilation but also may decrease vascular remodeling by limiting L-Orn production by native arginase.


Asunto(s)
Arginasa/metabolismo , Endotelio Vascular/metabolismo , Técnicas de Transferencia de Gen , Óxido Nítrico Sintasa de Tipo II/genética , Arteria Pulmonar/citología , Urea/metabolismo , Adenoviridae/genética , Animales , Arginasa/antagonistas & inhibidores , Arginina/farmacología , Bovinos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Perfilación de la Expresión Génica , Vectores Genéticos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Óxido Nítrico Sintasa de Tipo III/biosíntesis
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