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1.
J Forensic Sci ; 2023 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-37929668

RESUMEN

Dental identification is a pillar of disaster victim identification (DVI). Dental identification is accurate, efficient, inexpensive, and accepted in courts of law. The (known) antemortem (AM) dental charts and radiographic images acquired from the dentist of the missing person are evaluated, processed, and compared to post mortem (PM) findings present in the dentition or fragments of the dentition of the deceased individual. These comparisons evaluate and assess individuating restorative dental work, dental anatomical areas of concordance, spatial relationships of teeth one to another, and occasionally calculate the degree of "uniqueness" of either or both of the AM and PM dentition compared to known population databases. In a multiple fatality incident, odontologists may utilize age stratification to assist other means of identification. Computer comparison algorithms using recorded data can indicate possible matches between AM and PM data sets. Following clinical assessment, collection of post mortem tooth specimens for DNA profiling generation may be undertaken. This paper will highlight modern and efficient use of these tools. The framework for how dental identification in these incidents is currently managed is presented. The authors propose a change to this approach that moves away from interpretive subjective assessment toward comparisons based largely on objective data. The aim of this paper is to highlight the benefits of minimizing subjective decisions and maximizing objective data in the dental DVI process while simultaneously reducing risk to clinical personnel and minimizing costs by reducing the number of clinicians required onsite.

2.
J Am Dent Assoc ; 152(4): 284-292, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33637300

RESUMEN

BACKGROUND: With the advent of new ionizing radiation technologies, consideration must be given to the use of radiography in clinical practice. The authors aimed to determine how general dentists obtain oral and maxillofacial images and whether dentists' demographic characteristics and practice environments affect imaging decisions. METHODS: The authors conducted a cross-sectional study using an electronic survey to collect information from general dentists in Ontario, Canada's most populous province. RESULTS: The authors received 1,332 responses from 9,052 general dentists registered to practice in Ontario. A total of 57.2% of dentists used a nonindividualized approach to obtaining images for new adult dentate patients. Using clinical case scenarios, the authors found that 18.8% through 55.1% of dentists did not follow evidence-based guidelines when obtaining images. Overprescribing imaging was 5.8 times more common than underprescribing. Seeing patients after images were obtained (odds ratio [OR], 5.5), owning a panoramic and a cone-beam computed tomography imaging system (OR, 4.4), and the belief that images should be obtained to screen for occult pathoses (OR, 3.5) were the factors most strongly associated with overprescription. CONCLUSIONS: Radiography prescription practices varied considerably among general dentists in Ontario and did not conform to established guidelines. Factors other than patient needs appeared to influence imaging practices. PRACTICAL IMPLICATIONS: Overprescription of imaging by general dentists can result in unnecessary radiation exposure and financial costs to patients. To mitigate this, changes are needed in dental education, continuing education courses, and regulatory requirements.


Asunto(s)
Odontólogos , Pautas de la Práctica en Odontología , Adulto , Actitud del Personal de Salud , Estudios Transversales , Humanos , Ontario , Prescripciones , Radiografía , Encuestas y Cuestionarios
4.
Artículo en Inglés | MEDLINE | ID: mdl-32868255

RESUMEN

OBJECTIVE: The aim of this study was to determine the prevalence of 2-dimensional and 3-dimensional digital imaging technologies, the methods used by general dentists to limit patient exposure to ionizing radiation, and the impact of dentists' education on imaging technologies and patient dose-reducing techniques. STUDY DESIGN: A cross-sectional, web-based survey of all general dentists in Ontario was conducted. RESULTS: Responses from 1332 (14.7%) of the 9052 registered general dentists in Ontario were included in the analysis. Approximately 89% reported using digital intraoral technology, 81.1% reported owning panoramic imaging systems, 71.2% reported making referrals for cone beam computed tomography (CBCT), and 9.5% reported including CBCT in their practices. CBCT was most commonly used for dental implant treatment planning (85.8%), followed by endodontics (45.4%), evaluation of pathology (39.6%), and surgical assessment for impacted teeth or difficult extractions (36.8%). Approximately 32.7% used only collimators with a long focal point-receptor distance and 8% used only rectangular collimation; 86.9% reported using a thyroid collar when imaging patients. Differences in educational backgrounds correlated with differences in the use of imaging and dose-reducing techniques. CONCLUSIONS: There is widespread adoption of digital imaging technologies by general dentists in Ontario, including CBCT. Greater implementation of long and/or rectangular collimation could markedly reduce the ionizing radiation dose to patients. Changes in dental education curricula and continuing education course offerings may address these issues.


Asunto(s)
Tomografía Computarizada de Haz Cónico , Odontólogos , Estudios Transversales , Humanos , Ontario , Tecnología
5.
J Forensic Sci ; 66(2): 737-742, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33136292

RESUMEN

Comparison of post-mortem dental findings to ante mortem dental records is a well-established, frequently used scientific means of human identification. Dentistry has adapted a form of CT scanning that uses a cone-shaped beam and is thus termed cone beam computed tomography (CBCT). CBCT is presently being used in many aspects of dentistry including osseointegrated implant planning, orthodontics, endodontics, investigation of pathology, and assessment prior to complex dental extractions. The identification of seven individuals from multiple fatality incident was undertaken using a simple technique for completing comparative radiographic dental identifications using post-mortem medical computed tomographic (CT) image-acquisition techniques and commercially available dental software normally used in clinical care. The authors will show the means by which the harvesting of anatomically important data from medical CTs and conversion of these files was undertaken to provide crisp, clear post-mortem dental images for forensic comparison to assist in the identification of two adults and provide age stratification of three juveniles. The use of this technique has shown to be beneficial for expediting efficient identification of deceased individuals, helping to isolate which cases may need additional scientific methods of identification, saving time and money to the organization and eliminating biological/body substance or radiation exposure to the operator. The application of this software for use in forensic dental identification cases is presented, and the methodology to create post-mortem images suitable for comparison is detailed.


Asunto(s)
Tomografía Computarizada de Haz Cónico , Odontología Forense/métodos , Radiografía Panorámica/métodos , Tomografía Computarizada por Rayos X , Accidentes de Aviación , Adulto , Niño , Humanos , Imagenología Tridimensional , Programas Informáticos , Interfaz Usuario-Computador
6.
Sci Rep ; 10(1): 18309, 2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-33110111

RESUMEN

The pathogenesis of medication-related osteonecrosis of the jaw (MRONJ), a morbid condition associated with bisphosphonate administration, has not been fully elucidated. Recent research utilizing a murine model has revealed that the neutrophil becomes dysfunctional following exposure to bisphosphonates. Accordingly, the impairment of neutrophil function could play an important role in the pathogenesis of MRONJ via an infectious mechanism mediated by the suppression of the innate immune system. Currently, the existing human data are insufficient to substantiate this theory. To investigate, we isolated neutrophils from blood and oral rinse samples from bisphosphonate-naïve patients who were recently diagnosed with multiple myeloma both prior to and one month following their initial infusion of pamidronate, an intravenous bisphosphonate agent. Stimulated blood and oral neutrophil superoxide production and chemotactic capabilities were found to be impaired relative to baseline values. These results suggest that impaired neutrophil function may partially contribute to the aetiology underlying the pathophysiological processes linked to the development of MRONJ. Further, as the functional status of circulating neutrophils was reflected in the oral cavity where sampling can be accomplished in a non-invasive fashion, it is conceivable that neutrophil function could serve as a potential biomarker for MRONJ prognostication.


Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Pamidronato/farmacología , Estallido Respiratorio/efectos de los fármacos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Especies Reactivas de Oxígeno/metabolismo
7.
Am J Respir Crit Care Med ; 200(10): 1267-1281, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31215789

RESUMEN

Rationale: Complete tracheal ring deformity (CTRD) is a rare congenital abnormality of unknown etiology characterized by circumferentially continuous or nearly continuous cartilaginous tracheal rings, variable degrees of tracheal stenosis and/or shortening, and/or pulmonary arterial sling anomaly.Objectives: To test the hypothesis that CTRD is caused by inherited or de novo mutations in genes required for normal tracheal development.Methods: CTRD and normal tracheal tissues were examined microscopically to define the tracheal abnormalities present in CTRD. Whole-exome sequencing was performed in children with CTRD and their biological parents ("trio analysis") to identify gene variants in patients with CTRD. Mutations were confirmed by Sanger sequencing, and their potential impact on structure and/or function of encoded proteins was examined using human gene mutation databases. Relevance was further examined by comparison with the effects of targeted deletion of murine homologs important to tracheal development in mice.Measurements and Main Results: The trachealis muscle was absent in all of five patients with CTRD. Exome analysis identified six de novo, three recessive, and multiple compound-heterozygous or rare hemizygous variants in children with CTRD. De novo variants were identified in SHH (Sonic Hedgehog), and inherited variants were identified in HSPG2 (perlecan), ROR2 (receptor tyrosine kinase-like orphan receptor 2), and WLS (Wntless), genes involved in morphogenetic pathways known to mediate tracheoesophageal development in mice.Conclusions: The results of the present study demonstrate that absence of the trachealis muscle is associated with CTRD. Variants predicted to cause disease were identified in genes encoding Hedgehog and Wnt signaling pathway molecules, which are critical to cartilage formation and normal upper airway development in mice.


Asunto(s)
Mutación/genética , Anomalías del Sistema Respiratorio/genética , Tráquea/anomalías , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Humanos , Ratones , Anomalías del Sistema Respiratorio/diagnóstico , Anomalías del Sistema Respiratorio/cirugía
8.
Laryngoscope ; 129(1): 244-255, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30152166

RESUMEN

OBJECTIVES: Develop multidisciplinary and international consensus on patient, disease, procedural, and perioperative factors, as well as key outcome measures and complications, to be reported for pediatric airway reconstruction studies. METHODS: Standard Delphi methods were applied. Participants proposed items in three categories: 1) patient/disease characteristics, 2) procedural/intraoperative/perioperative factors, and 3) outcome measures and complications. Both general and anatomic site-specific measures were elicited. Participants also suggested specific operations to be encompassed by this project. We then used iterative ranking and review to develop consensus lists via a priori Delphi consensus criteria. RESULTS: Thirty-three pediatric airway experts from eight countries in North and South America, Europe, and Australia participated, representing otolaryngology (including International Pediatric Otolaryngology Group members), pulmonology, general surgery, and cardiothoracic surgery. Consensus led to inclusion of 19 operations comprising open expansion, resection, and slide procedures of the larynx, trachea, and bronchi as well as three endoscopic procedures. Consensus was achieved on multiple patient/comorbidity (10), disease/stenosis (7), perioperative-/intraoperative-/procedure-related (16) factors. Consensus was reached on multiple outcome and complication measures, both general and site-specific (8 general, 13 supraglottic, 15 glottic, 17 subglottic, 8 cervical tracheal, 12 thoracic tracheal). The group was able to clarify how each outcome should be measured, with specific instruments defined where applicable. CONCLUSION: This consensus statement provides a framework to communicate results consistently and reproducibly, facilitating meta-analyses, quality improvement, transfer of information, and surgeon self-assessment. It also clarifies expert opinion on which patient, disease, procedural, and outcome measures may be important to consider in any pediatric airway reconstruction patient. LEVEL OF EVIDENCE: 5 Laryngoscope, 129:244-255, 2019.


Asunto(s)
Laringoplastia/normas , Laringe/cirugía , Procedimientos Quirúrgicos Otorrinolaringológicos/normas , Evaluación de Resultado en la Atención de Salud , Procedimientos de Cirugía Plástica/normas , Tráquea/cirugía , Niño , Técnica Delphi , Humanos , Procedimientos Quirúrgicos Otorrinolaringológicos/métodos , Evaluación de Resultado en la Atención de Salud/métodos , Pediatría , Guías de Práctica Clínica como Asunto , Procedimientos de Cirugía Plástica/métodos , Reoperación
10.
J Am Dent Assoc ; 149(6): 470-480, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29606275

RESUMEN

BACKGROUND: Dentists are generally taught that in a significant number of patients with newly diagnosed acute leukemia (NDAL), the diagnosis may be suspected based on oral signs. In this study, the authors determined the frequency of oral signs of leukemia and tabulated the clinical dental needs and hematologic aspects of these patients. METHODS: Four calibrated dentists performed clinical examinations in 263 consecutive patients with NDAL. A standardized data form was used to direct and record presence or absence of oral signs of leukemia, clinically apparent dental disease, and circulating blood counts. RESULTS: Oral signs of leukemia were detected on oral examination in 30.8% (95% confidence interval [CI], 25.2% to 36.4%) of patients with NDAL on examination. Only 5.7% (95% CI, 2.9% to 8.5%) of patients had gingival enlargement (GE). Although 33.7% (95% CI, 26.6% to 40.9%) of regular dental treatment seekers and 55.3% (95% CI, 45.3% to 65.4%) of nonregular dental treatment seekers had clinically detectable dental disease, only 18.6% (95% CI, 13.9% to 23.3%) had circulating blood counts that precluded all but urgent oral health care. CONCLUSION: Although 30.8% of patients examined had some oral sign of leukemia, most adults with NDAL do not have GE at the initial examination. Even patients receiving regular oral health care may have unmet dental needs at the initial assessment that could safely be addressed before treatment. PRACTICAL IMPLICATIONS: Dentists should not necessarily expect to be able to detect overt oral signs of leukemia, such as GE, in patients with NDAL on oral examination. Once patients receive the diagnosis, dentists may be able to safely eliminate dental disease in most patients in an appropriate setting. Dentists are encouraged to undertake a thorough review of systems.


Asunto(s)
Leucemia , Salud Bucal , Adulto , Odontólogos , Diagnóstico Bucal , Humanos , Prevalencia
11.
Pediatrics ; 141(3)2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29437862

RESUMEN

Aerodigestive programs provide coordinated interdisciplinary care to pediatric patients with complex congenital or acquired conditions affecting breathing, swallowing, and growth. Although there has been a proliferation of programs, as well as national meetings, interest groups and early research activity, there is, as of yet, no consensus definition of an aerodigestive patient, standardized structure, and functions of an aerodigestive program or a blueprint for research prioritization. The Delphi method was used by a multidisciplinary and multi-institutional panel of aerodigestive providers to obtain consensus on 4 broad content areas related to aerodigestive care: (1) definition of an aerodigestive patient, (2) essential construct and functions of an aerodigestive program, (3) identification of aerodigestive research priorities, and (4) evaluation and recognition of aerodigestive programs and future directions. After 3 iterations of survey, consensus was obtained by either a supermajority of 75% or stability in median ranking on 33 of 36 items. This included a standard definition of an aerodigestive patient, level of participation of specific pediatric disciplines in a program, essential components of the care cycle and functions of the program, feeding and swallowing assessment and therapy, procedural scope and volume, research priorities and outcome measures, certification, coding, and funding. We propose the first consensus definition of the aerodigestive care model with specific recommendations regarding associated personnel, infrastructure, research, and outcome measures. We hope that this may provide an initial framework to further standardize care, develop clinical guidelines, and improve outcomes for aerodigestive patients.


Asunto(s)
Enfermedades Gastrointestinales/terapia , Grupo de Atención al Paciente/organización & administración , Desarrollo de Programa , Enfermedades Respiratorias/terapia , Niño , Técnica Delphi , Investigación sobre Servicios de Salud/organización & administración , Humanos , Investigación Interdisciplinaria/organización & administración , Terminología como Asunto , Estados Unidos
13.
Head Neck ; 39(10): 2016-2020, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28703386

RESUMEN

BACKGROUND: Radiologic assessment of mandibular bone invasion is critical in evaluating the extent of bone resection required in patients with oral cancer. There are a few reports of improved sensitivity with cone-beam CT (CBCT) over conventional CT. METHODS: A prospective cohort study of patients with oral squamous cell carcinomas adjacent to the mandible requiring marginal or segmental mandibular resection was performed. Patients were treated based on clinical assessment and conventional cross-sectional imaging. Patients and surgeons were blinded to the results of CBCT performed preoperatively. Pathologic examination served as the gold standard. RESULTS: Forty-five patients were included in the study. Thirty-three percent of the patients underwent segmental mandibulectomy and 37% had bone invasion. The sensitivity and specificity of CBCT were 91% and 60%, respectively, compared to 86% and 68% for CT with bone windows. CONCLUSION: A CBCT offers marginally improved sensitivity at the cost of reduced specificity for assessment of bone invasion compared to CT.


Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Neoplasias Mandibulares/secundario , Neoplasias de la Boca/patología , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/diagnóstico por imagen , Estudios de Cohortes , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Humanos , Masculino , Mandíbula/patología , Mandíbula/cirugía , Neoplasias Mandibulares/diagnóstico por imagen , Neoplasias Mandibulares/cirugía , Osteotomía Mandibular/métodos , Persona de Mediana Edad , Neoplasias de la Boca/diagnóstico por imagen , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Estudios Prospectivos , Sensibilidad y Especificidad , Carcinoma de Células Escamosas de Cabeza y Cuello
14.
Clin Transplant ; 31(6)2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28316109

RESUMEN

OBJECTIVES: To describe the upper airway endoscopic findings of children with upper airway symptoms after liver transplantation (LT) or heart transplantation (HT). METHODS: Review of children undergoing airway endoscopy after LT or HT from 2011 to 2015 at a tertiary care pediatric hospital. Airway findings, biopsy results, immunosuppression, and Epstein-Barr virus (EBV) levels were recorded. RESULTS: Twenty-three of 158 LT (111) and HT (47) recipients underwent endoscopy. Median time from LT to endoscopy was 9 months (range 4-25) and 31 months (range 1-108) for HT. Thirteen of 23 patients presented with upper airway symptoms, and 10/23 presented with respiratory failure or for surveillance. Thirteen patients with upper airway symptoms had abnormal findings (7 LT; 6 HT), most commonly arytenoid edema (13 patients). There were five EBV-positive biopsies (four with post-transplant lymphoproliferative disorder), and six EBV-negative biopsies with lymphocytic inflammation. One biopsy demonstrated fungal infection. Immunosuppression was decreased in seven patients, and three received steroids. There were no episodes of allograft rejection. No patients had airway symptoms at last follow-up. CONCLUSIONS: In pediatric solid organ transplant recipients, symptoms of airway obstruction are not uncommon and should be evaluated with endoscopy. Endoscopy without symptoms is low-yield. Treatment with decreased immunosuppression improved airway symptoms.


Asunto(s)
Infecciones por Virus de Epstein-Barr/etiología , Trasplante de Corazón/efectos adversos , Inflamación/etiología , Trasplante de Hígado/efectos adversos , Trastornos Linfoproliferativos/etiología , Complicaciones Posoperatorias , Enfermedades Respiratorias/etiología , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Supervivencia de Injerto , Herpesvirus Humano 4/patogenicidad , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Factores de Riesgo
15.
Pediatr Pulmonol ; 52(1): E1-E3, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27333290

RESUMEN

Traumatic injuries to the pediatric trachea are uncommon events that require prompt diagnosis and management. When they do occur, tracheal injuries often arise in the setting of high impact trauma and are accompanied by major injuries to other organ systems. In this report, we present the diagnosis and conservative management of tracheal rupture at the carina in an 11-year-old female with severe intracranial injuries. Pediatr Pulmonol. 2017;52:E1-E3. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Broncoscopía , Tratamiento Conservador , Intubación Intratraqueal , Enfermedades de la Tráquea/terapia , Niño , Femenino , Humanos , Rotura , Tráquea , Enfermedades de la Tráquea/diagnóstico , Resultado del Tratamiento
16.
Front Psychol ; 7: 1065, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27486415

RESUMEN

A Bayesian technique with analyses of within-person processes at the level of the individual is presented. The approach is used to examine whether the patterns of within-person responses on a 12-trial simulation task are consistent with the predictions of ITA theory (Dweck, 1999). ITA theory states that the performance of an individual with an entity theory of ability is more likely to spiral down following a failure experience than the performance of an individual with an incremental theory of ability. This is because entity theorists interpret failure experiences as evidence of a lack of ability which they believe is largely innate and therefore relatively fixed; whilst incremental theorists believe in the malleability of abilities and interpret failure experiences as evidence of more controllable factors such as poor strategy or lack of effort. The results of our analyses support ITA theory at both the within- and between-person levels of analyses and demonstrate the benefits of Bayesian techniques for the analysis of within-person processes. These include more formal specification of the theory and the ability to draw inferences about each individual, which allows for more nuanced interpretations of individuals within a personality category, such as differences in the individual probabilities of spiraling. While Bayesian techniques have many potential advantages for the analyses of processes at the level of the individual, ease of use is not one of them for psychologists trained in traditional frequentist statistical techniques.

18.
Am J Respir Crit Care Med ; 191(9): 1066-80, 2015 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-25932763

RESUMEN

BACKGROUND: Flexible airway endoscopy (FAE) is an accepted and frequently performed procedure in the evaluation of children with known or suspected airway and lung parenchymal disorders. However, published technical standards on how to perform FAE in children are lacking. METHODS: The American Thoracic Society (ATS) approved the formation of a multidisciplinary committee to delineate technical standards for performing FAE in children. The committee completed a pragmatic synthesis of the evidence and used the evidence synthesis to answer clinically relevant questions. RESULTS: There is a paucity of randomized controlled trials in pediatric FAE. The committee developed recommendations based predominantly on the collective clinical experience of our committee members highlighting the importance of FAE-specific airway management techniques and anesthesia, establishing suggested competencies for the bronchoscopist in training, and defining areas deserving further investigation. CONCLUSIONS: These ATS-sponsored technical standards describe the equipment, personnel, competencies, and special procedures associated with FAE in children.


Asunto(s)
Manejo de la Vía Aérea/normas , Competencia Clínica/normas , Endoscopía/normas , Enfermedades Respiratorias/diagnóstico , Sociedades Médicas/normas , Adolescente , Niño , Preescolar , Femenino , Tecnología de Fibra Óptica , Humanos , Masculino , Estados Unidos
19.
Nature ; 514(7523): 450-4, 2014 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-25274301

RESUMEN

Bone-marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independently of haematological progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor-ß-deficient (Csf2rb(-/-)) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA or CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe and well-tolerated and that one administration corrected the lung disease, secondary systemic manifestations and normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Our findings identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP.


Asunto(s)
Trasplante de Células , Subunidad beta Común de los Receptores de Citocinas/genética , Terapia Genética , Pulmón/citología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/trasplante , Proteinosis Alveolar Pulmonar/terapia , Animales , Separación Celular , Subunidad beta Común de los Receptores de Citocinas/deficiencia , Femenino , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Proteinosis Alveolar Pulmonar/genética , Proteinosis Alveolar Pulmonar/patología , Factores de Tiempo
20.
Am J Respir Crit Care Med ; 189(2): 183-93, 2014 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-24279752

RESUMEN

RATIONALE: In patients with pulmonary alveolar proteinosis (PAP) syndrome, disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling is associated with pathogenic surfactant accumulation from impaired clearance in alveolar macrophages. OBJECTIVES: The aim of this study was to overcome these barriers by using monocyte-derived induced pluripotent stem (iPS) cells to recapitulate disease-specific and normal macrophages. METHODS: We created iPS cells from two children with hereditary PAP (hPAP) caused by recessive CSF2RA(R217X) mutations and three normal people, differentiated them into macrophages (hPAP-iPS-Mφs and NL-iPS-Mφs, respectively), and evaluated macrophage functions with and without gene-correction to restore GM-CSF signaling in hPAP-iPS-Mφs. MEASUREMENTS AND MAIN RESULTS: Both hPAP and normal iPS cells had human embryonic stem cell-like morphology, expressed pluripotency markers, formed teratomas in vivo, had a normal karyotype, retained and expressed mutant or normal CSF2RA genes, respectively, and could be differentiated into macrophages with the typical morphology and phenotypic markers. Compared with normal, hPAP-iPS-Mφs had impaired GM-CSF receptor signaling and reduced GM-CSF-dependent gene expression, GM-CSF- but not M-CSF-dependent cell proliferation, surfactant clearance, and proinflammatory cytokine secretion. Restoration of GM-CSF receptor signaling corrected the surfactant clearance abnormality in hPAP-iPS-Mφs. CONCLUSIONS: We used patient-specific iPS cells to accurately reproduce the molecular and cellular defects of alveolar macrophages that drive the pathogenesis of PAP in more than 90% of patients. These results demonstrate the critical role of GM-CSF signaling in surfactant homeostasis and PAP pathogenesis in humans and have therapeutic implications for hPAP.


Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Células Madre Pluripotentes Inducidas/metabolismo , Proteinosis Alveolar Pulmonar/fisiopatología , Surfactantes Pulmonares/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Estudios de Casos y Controles , Diferenciación Celular , Células Cultivadas , Niño , Técnicas de Transferencia de Gen , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Humanos , Macrófagos Alveolares/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Transducción de Señal
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