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The paediatric metaphysis is afflicted by a wide range of pathological processes as it is the most metabolically active and well-vascularised part of the developing skeleton. This review focuses on metaphyseal marrow signal change detected with magnetic resonance imaging, which is most often occult on radiographs. When bilateral, these imaging appearances frequently present a diagnostic quandary. This review assists the radiologist to confidently dismiss physiological signal change and confidently work through the differential diagnosis. This is achieved by illustrating a practical method of classifying signal change into four categories: physiological red marrow, red marrow reconversion, marrow infiltration, and oedema-like marrow signal intensity. In doing so, various pathological entities are reviewed along with imaging pearls and next-step investigations.
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Enfermedades de la Médula Ósea , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Enfermedades de la Médula Ósea/diagnóstico por imagen , Diagnóstico Diferencial , Niño , Médula Ósea/diagnóstico por imagen , Médula Ósea/patología , Masculino , Femenino , Preescolar , LactanteRESUMEN
Whereas traditional histology and light microscopy require multiple steps of formalin fixation, paraffin embedding, and sectioning to generate images for pathologic diagnosis, Microscopy using Ultraviolet Surface Excitation (MUSE) operates through UV excitation on the cut surface of tissue, generating images of high resolution without the need to fix or section tissue and allowing for potential use for downstream molecular tests. Here, we present the first study of the use and suitability of MUSE microscopy for neuropathological samples. MUSE images were generated from surgical biopsy samples of primary and metastatic brain tumor biopsy samples (n = 27), and blinded assessments of diagnoses, tumor grades, and cellular features were compared to corresponding hematoxylin and eosin (H&E) images. A set of MUSE-treated samples subsequently underwent exome and targeted sequencing, and quality metrics were compared to those from fresh frozen specimens. Diagnostic accuracy was relatively high, and DNA and RNA integrity appeared to be preserved for this cohort. This suggests that MUSE may be a reliable method of generating high-quality diagnostic-grade histologic images for neuropathology on a rapid and sample-sparing basis and for subsequent molecular analysis of DNA and RNA.
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BACKGROUND: The aim of this study was to assess the clinical impact of indeterminate pulmonary nodules (no more than four pulmonary nodules of less than 5 mm or one nodule measuring between 5 and less than 10 mm by computed tomography [CT]) in children and adolescents with adult-type non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) at diagnosis. METHODS: Patients with NRSTS treated in 11 centers as part of the European paediatric Soft Tissue Sarcoma Study Group (EpSSG) were retrospectively assessed. Local radiologists, blinded to clinical information except for patients' age and tumor histotype, reviewed the chest CT at diagnosis and filled out a case report form. Because patients with or without indeterminate nodules in the EpSSG NRSTS 2005 study received the same type of treatment, event-free survival (EFS) and overall survival (OS) between groups by log-rank test were compared. RESULTS: Overall, 206 patients were examined: 109 (52.9%) were without any nodules, 78 (38%) had at least one indeterminate nodule, and 19 (9.2%) had nodules meeting the definition of metastases, which were then considered to be misclassified and were excluded from further analyses. Five-year EFS was 78.5% (95% CI, 69.4%-85.1%) for patients without nodules and 69.6% (95% CI, 57.9%-78.7%) for patients with indeterminate nodules (p = .135); 5-year OS was 87.4% (95% CI, 79.3%-92.5%) and 79.0% (95% CI, 67.5%-86.8%), respectively (p = .086). CONCLUSIONS: This study suggests that survival does not differ in otherwise nonmetastatic patients with indeterminate pulmonary nodules compared to nonmetastatic patients without pulmonary nodules. PLAIN LANGUAGE SUMMARY: Radiologists should be aware of the classification of indeterminate pulmonary nodules in non-rhabdomyosarcoma soft tissue sarcomas and use it in their reports. More than a third of patients with non-rhabdomyosarcoma soft tissue sarcoma can be affected by indeterminate pulmonary nodules. Indeterminate pulmonary nodules do not significantly affect the overall survival of pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma.
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Rabdomiosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Niño , Adulto , Adolescente , Estudios Retrospectivos , Sarcoma/tratamiento farmacológico , Rabdomiosarcoma/terapia , Neoplasias de los Tejidos Blandos/patología , Supervivencia sin ProgresiónRESUMEN
Background and purpose: Children receiving radiotherapy for head-and-neck tumours often experience severe dentofacial side effects. Despite this, recommendations for contouring and dose constraints to dentofacial structures are lacking in clinical practice. We report on a survey aiming to understand current practice in contouring and dose assessment to dentofacial structures. Methods: A digital survey was distributed to European Society for Paediatric Oncology members of the Radiation Oncology Working Group, and member-affiliated centres in Europe, Australia, and New Zealand. The questions focused on clinical practice and aimed to establish areas for future development. Results: Results from 52 paediatric radiotherapy centres across 27 countries are reported. Only 29/52 centres routinely delineated some dentofacial structures, with the most common being the mandible (25 centres), temporo-mandibular joint (22), dentition (13), orbit (10) and maxillary bone (eight). For most bones contoured, an 'As Low As Reasonably Achievable' dose objective was implemented. Only four centres reported age-adapted dose constraints.The largest barrier to clinical implementation of dose constraints was firstly, the lack of contouring guidance (49/52, 94%) and secondly, that delineation is time-consuming (33/52, 63%). Most respondents who routinely contour dentofacial structures (25/27, 90%) agreed a contouring atlas would aid delineation. Conclusion: Routine delineation of dentofacial structures is infrequent in paediatric radiotherapy. Based on survey findings, we aim to 1) define a consensus-contouring atlas for dentofacial structures, 2) develop auto-contouring solutions for dentofacial structures to aid clinical implementation, and 3) carry out treatment planning studies to investigate the importance of delineation of these structures for planning optimisation.
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Inflammatory bowel disease (IBD) pathogenesis is thought to be induced by a mix of genetic susceptibility, microbial populations, and immune triggers such as infections. Severe acute respiratory syndrome coronavirus 2 (SARS-nCoV2) may have increased capacity to generate autoimmune disease as evidenced by known spikes in diseases such as type 1 diabetes mellitus. Public health interventions like masking and closures additionally created remarkable drops in typical viral infections, with remarkable shifts in influenza-like illness reporting in 2020. This study aims to evaluate the impact of SARS-nCoV2 and associated interventions on pediatric IBD presentation in New York City using records of new diagnoses at a consortium of 4 institutions between 2016 and June 2022. We fit time series model (autoregressive integrated moving average model) to monthly and quarterly number of cases of each disease for January 2016-March 2020 and forecast the period between April 2020 and June 2022. We note no decrease in ulcerative colitis (UC) or Crohn disease (CD) in the aftermath of historic low levels of overall viral illness, and statistically significant increases in CD diagnoses and elevation in UC diagnoses creating a trend suggesting overall increase in IBD diagnoses exceeding the baseline rate of increase. These data suggest a possible linkage between SARS-nCoV2 infection rates and subsequent pediatric IBD presentation.
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COVID-19 , Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Niño , COVID-19/epidemiología , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedad de Crohn/diagnóstico , Colitis Ulcerosa/diagnóstico , Ciudad de Nueva York/epidemiologíaRESUMEN
The apical junction of epithelial cells can generate force to control cell geometry and perform contractile processes while maintaining barrier function and adhesion. Yet, the structural basis for force generation at the apical junction is not fully understood. Here, we describe two synaptopodin-dependent actomyosin structures that are spatially, temporally, and structurally distinct. The first structure is formed by the retrograde flow of synaptopodin initiated at the apical junction, creating a sarcomeric stress fiber that lies parallel to the apical junction. Contraction of the apical stress fiber is associated with either clustering of membrane components or shortening of junctional length. Upon junction maturation, apical stress fibers are disassembled. In mature epithelial monolayer, a motorized "contractomere" capable of "walking the junction" is formed at the junctional vertex. Actomyosin activities at the contractomere produce a compressive force evident by actin filament buckling and measurement with a new α-actinin-4 force sensor. The motility of contractomeres can adjust junctional length and change cell packing geometry during cell extrusion and intercellular movement. We propose a model of epithelial homeostasis that utilizes contractomere motility to support junction rearrangement while preserving the permeability barrier.
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Actomiosina , Células Epiteliales , Uniones Intercelulares , Proteínas de Microfilamentos , Fibras de Estrés , Citoesqueleto de Actina/metabolismo , Actomiosina/metabolismo , Células Epiteliales/metabolismo , Uniones Intercelulares/metabolismo , Proteínas de Microfilamentos/metabolismo , Fibras de Estrés/metabolismoRESUMEN
Abnormalities of the sternum and adjacent structures are an uncommon presentation in the paediatric population and can have a variety of benign and malignant causes, including normal and developmental variants of the chest wall. Although there is overlap with adults, many sternal abnormalities are unique to the paediatric population. Following clinical examination, radiography is usually the first type of imaging used; however, it is limited and often ultrasound and cross-sectional imaging are needed for further assessment. An understanding of the normal anatomy is important; however, this can be challenging due to the varied appearances of age-related changes of the sternum. The purpose of this article is to familiarize the general paediatric radiologist with the expected anatomy and imaging findings of the developing sternum, anatomical variants and pathology of the sternum and adjacent structures encountered in this group of patients.
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Enfermedades Óseas , Enfermedades Torácicas , Pared Torácica , Adulto , Enfermedades Óseas/patología , Niño , Humanos , Esternón/diagnóstico por imagen , Esternón/patología , Tomografía Computarizada por Rayos XRESUMEN
We report on the location, symptoms, and management of plexiform neurofibroma (PN) in children with Neurofibromatosis Type 1 (NF1) attending the 2 National Complex Neurofibromatosis 1 Services at Guy's and St. Thomas' NHS Foundation Trust, London and St Mary's Hospital, Manchester. Retrospective data collection was performed from patient chart reviews from April 2018 to April 2019. There were 127 NF1 patients with PN, age range 0.8-17.0, mean age was 9.9 years (SD ± 4.2 years). The main location of the PN was craniofacial in 35%, and limb in 19%. Disfigurement was present in 57%, pain in 28%, impairment of function in 23%, and threat to function in 9% of children. Fifty-four percent of patients were managed conservatively, 28% surgically, and 19% are either taking or due to start a mitogen-activated protein kinase kinase (MEK) inhibitor (selumetinib or trametinib), either through a clinical trial or compassionate usage scheme. This national study provides a comprehensive overview of the management of children with PN in an era where new therapies (MEK inhibitors) are becoming more widely available. We anticipate that there will be a shift to more patients receiving MEK inhibitor therapy and combination therapy (surgery and MEK inhibitor) in the future.
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Neurofibroma Plexiforme , Neurofibromatosis 1 , Adolescente , Niño , Preescolar , Humanos , Lactante , Quinasas de Proteína Quinasa Activadas por Mitógenos , Neurofibroma Plexiforme/epidemiología , Neurofibroma Plexiforme/terapia , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios RetrospectivosRESUMEN
The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain.
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Interneuronas/fisiología , Eminencia Media/embriología , Células-Madre Neurales/fisiología , Neurogénesis , Prosencéfalo/citología , Animales , Animales Recién Nacidos , Movimiento Celular , Proliferación Celular , Corteza Cerebral/citología , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Neuronas GABAérgicas/citología , Neuronas GABAérgicas/fisiología , Perfilación de la Expresión Génica , Edad Gestacional , Humanos , Interneuronas/citología , Eminencia Media/citología , Eminencia Media/crecimiento & desarrollo , Ratones , Células-Madre Neurales/trasplante , Prosencéfalo/embriología , Prosencéfalo/crecimiento & desarrollo , Trasplante HeterólogoRESUMEN
The first reported malignancy associated with Cockayne syndrome.
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Síndrome de Cockayne , Neoplasias Hepáticas , Sarcoma , Síndrome de Cockayne/complicaciones , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/genética , Femenino , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Sarcoma/complicaciones , Sarcoma/diagnóstico , Sarcoma/genéticaRESUMEN
Cadherins harness the actin cytoskeleton to build cohesive sheets of cells using paradoxically weak bonds, but the molecular mechanisms are poorly understood. In one popular model, actin organizes cadherins into large, micrometer-sized clusters known as puncta. Myosin is thought to pull on these puncta to generate strong adhesion. Here, however, we show that cadherin puncta are actually interdigitated actin microspikes generated by actin polymerization mediated by three factors (Arp2/3, EVL, and CRMP-1). The convoluted membranes in these regions give the impression of cadherin clustering by fluorescence microscopy, but the ratio of cadherin to membrane is constant. Nevertheless, these interlocking fingers of membrane are important for adhesion because perturbing their formation disrupts cell adhesion. In contrast, blocking myosin-dependent contractility does not disrupt either the interdigitated microspikes or lateral membrane adhesion. "Puncta" are zones of strong cell-cell adhesion not due to cadherin clustering but that occur because the interdigitated microspikes expand the surface area available for adhesive bond formation and increase the asperity of the cell surface to promote friction between cells.
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Actinas/metabolismo , Cadherinas/metabolismo , Extensiones de la Superficie Celular/metabolismo , Animales , Adhesión Celular , Extensiones de la Superficie Celular/ultraestructura , Perros , Recuperación de Fluorescencia tras Fotoblanqueo , Proteínas Fluorescentes Verdes/metabolismo , Imagenología Tridimensional , Células de Riñón Canino Madin Darby , Miosinas/metabolismo , PolimerizacionRESUMEN
BACKGROUND: Nephroblastomatosis is a recognised precursor for the development of Wilms tumour (WT), the most common childhood renal tumour. While the majority of WT is sporadic in origin, germline intragenic mutations of predisposition genes such as WT1, REST and TRIM28 have been described in apparently isolated (non-familial) WT.Despite constitutional CNVs being a well-studied cause of developmental disorders, their role in cancer predisposition is less well defined, so that the interpretation of cancer risks associated with specific CNVs can be complex. OBJECTIVE: To highlight the role of a constitutional deletion CNV (delCNV) encompassing the REST tumour suppressor gene in diffuse hyperplastic perilobar nephroblastomatosis (HPLN). METHODS/RESULTS: Array comparative genomic hybridisation in an infant presenting with apparently sporadic diffuse HPLN revealed a de novo germline CNV, arr[GRCh37] 4q12(57,385,330-57,947,405)x1. The REST tumour suppressor gene is located at GRCh37 chr4:57,774,042-57,802,010. CONCLUSION: This delCNV encompassing REST is associated with nephroblastomatosis. Deletion studies should be included in the molecular work-up of inherited predisposition to WT/nephroblastomatosis. Detection of delCNVs involving known cancer predisposition genes can yield insights into the relationship between underlying genomic architecture and associated tumour risk.
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Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Proteínas Represoras/genética , Eliminación de Secuencia , Biopsia , Hibridación Genómica Comparativa , Análisis Citogenético , Femenino , Estudios de Asociación Genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lactante , Neoplasias Renales/cirugía , Imagen por Resonancia Magnética , FenotipoRESUMEN
Atypical teratoid/rhabdoid tumor (AT/RT) is a rare central nervous system (CNS) tumor diagnosed primarily in infants and usually portends a poor prognosis. Despite being the most common embryonal tumor in children less than 1 year old, diagnosis is difficult to make based on clinical findings or imaging alone. A complete diagnosis of AT/RT requires identification of loss of integrase interactor 1 (INI1) protein or the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) gene, in its most common presentation. Moreover, their presentation with other primary rhabdoid tumors in the body raises significant suspicion for rhabdoid tumor predisposition syndrome (RTPS). We report a case of a one-month-old infant admitted for worsening emesis and failure to thrive, who was later found to have brain and bladder masses on radiologic imaging. Autopsy with subsequent immunoprofile and molecular testing were crucial in establishing the absence of INI1 nuclear expression and possible homozygous deletion of SMARCB1 in the urinary bladder tumor tissue. Sequencing of the peripheral blood demonstrated probable single copy loss at the SMARCB1 locus. The constellation of findings in tumor and peripheral blood sequencing suggested the possibility of germline single copy SMARCB1 loss, followed by somatic loss of the remaining SMARCB1 allele due to copy neutral loss-of-heterozygosity. Such a sequence of genetic events has been described in malignant rhabdoid tumors (MRT). Dedicated germline testing of this patient's family members could yield answers as to whether rhabdoid tumor predisposition syndrome will continue to have implications for the patient's family.
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Cyclic vomiting syndrome is an idiopathic chronic periodic disorder of childhood which may persist into the adult years. Although cyclic vomiting syndrome is considered a central nervous system disorder, it is often managed by a pediatric gastroenterologist. The practitioner should not assume a gastrointestinal or non-neurological cause of symptoms especially if there are coexisting neurological symptoms and signs or if vomiting does not bring relief; this suggests a possible central nervous system cause, which may necessitate a pediatric neurology consultation. Examples of central nervous system causes of cyclic vomiting syndrome that can have subjective and objective neurological findings include abdominal migraine, certain types of epilepsy, structural lesions (tumors, Chiari malformation, demyelinating disease), mitochondrial disease, autonomic disorders, fatty acid/organic acid disorders, urea cycle defects, and cannabinoid hyperemesis syndrome. Improved familiarity with cyclic vomiting syndrome and its mimics may improve the time to appropriate diagnosis and may reduce morbidity related to cyclic vomiting syndrome.
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Enfermedades del Sistema Nervioso Autónomo/complicaciones , Enfermedades del Sistema Nervioso Central/complicaciones , Enfermedades Metabólicas/complicaciones , Vómitos/etiología , Niño , Humanos , Vómitos/fisiopatologíaRESUMEN
Atypical teratoid/rhabdoid tumor (AT/RT) is a rare central nervous system (CNS) tumor diagnosed primarily in infants and usually portends a poor prognosis. Despite being the most common embryonal tumor in children less than 1 year old, diagnosis is difficult to make based on clinical findings or imaging alone. A complete diagnosis of AT/RT requires identification of loss of integrase interactor 1 (INI1) protein or the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) gene, in its most common presentation. Moreover, their presentation with other primary rhabdoid tumors in the body raises significant suspicion for rhabdoid tumor predisposition syndrome (RTPS). We report a case of a one-month-old infant admitted for worsening emesis and failure to thrive, who was later found to have brain and bladder masses on radiologic imaging. Autopsy with subsequent immunoprofile and molecular testing were crucial in establishing the absence of INI1 nuclear expression and possible homozygous deletion of SMARCB1 in the urinary bladder tumor tissue. Sequencing of the peripheral blood demonstrated probable single copy loss at the SMARCB1 locus. The constellation of findings in tumor and peripheral blood sequencing suggested the possibility of germline single copy SMARCB1 loss, followed by somatic loss of the remaining SMARCB1 allele due to copy neutral loss-of-heterozygosity. Such a sequence of genetic events has been described in malignant rhabdoid tumors (MRT). Dedicated germline testing of this patient's family members could yield answers as to whether rhabdoid tumor predisposition syndrome will continue to have implications for the patient's family.
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Humanos , Femenino , Lactante , Neoplasias Encefálicas/patología , Tumor Rabdoide/patología , Autopsia , Neoplasias de la Vejiga Urinaria/patología , Resultado FatalRESUMEN
The epithelial lateral membrane plays a central role in the integration of intercellular signals and, by doing so, is a principal determinant in the emerging properties of epithelial tissues. Mechanical force, when applied to the lateral cell-cell interface, can modulate the strength of adhesion and influence intercellular dynamics. Yet the relationship between mechanical force and epithelial cell behavior is complex and not completely understood. This commentary aims to provide an investigative look at the usage of cellular forces at the epithelial cell-cell adhesion interface.
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Fenómenos Biomecánicos , Adhesión Celular/fisiología , Epitelio/fisiología , Animales , Extensiones de la Superficie Celular , Células Epiteliales , Humanos , Contracción MuscularRESUMEN
Actomyosin II contractility in epithelial cell plays an essential role in tension-dependent adhesion strengthening. One key unsettling question is how cellular contraction transmits force to the nascent cell-cell adhesion when there is no stable attachment between the nascent adhesion complex and actin filament. Here, we show that myosin-1c is localized to the lateral membrane of polarized epithelial cells and facilitates the coupling between actin and cell-cell adhesion. Knockdown of myosin-1c compromised the integrity of the lateral membrane, reduced the generation of tension at E-cadherin, decreased the strength of cell-cell cohesion in an epithelial cell monolayer and prevented force-dependent recruitment of junctional α-actinin. Application of exogenous force to cell-cell adhesions in a myosin-1c-knockdown cell monolayer fully rescued the localization defect of α-actinin, indicating that junction mechanoregulation remains intact in myosin-1c-depleted cells. Our study identifies a role of myosin-1c in force transmission at the lateral cell-cell interface and underscores a non-junctional contribution to tension-dependent junction regulation.
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Actinina/metabolismo , Cadherinas/metabolismo , Células Epiteliales/metabolismo , Uniones Intercelulares/metabolismo , Miosina Tipo II/metabolismo , HumanosRESUMEN
OBJECTIVES: A simple and reliable biomarker for Crohn disease (CD) would be a valuable clinical tool. We hypothesized that anti-Saccharomyces cerevisiae antibody (ASCA) may be present in the stool of patients with CD. Accordingly, we measured ASCA in the stool and serum of children and adolescents with known or suspected inflammatory bowel disease (IBD). METHODS: We included 114 patients 19 years or younger (73 boys) with IBD, including 83 patients with CD and 31 subjects without CD (28 with ulcerative colitis, and 3 patients with suspected IBD but without evidence of chronic inflammation at the time of their endoscopy and colonoscopy). Fecal and serum samples were analyzed using semiquantitative ASCA enzyme-linked immunoassays. RESULTS: Median ASCA levels were significantly elevated in the stool (Pâ=â0.04) and serum (Pâ=â0.0008) of patients with CD, when compared to levels observed in patients without CD. Fecal ASCA levels were similarly more elevated in patients with active CD, relative to levels observed in patients with active ulcerative colitis and acute colitis (Pâ=â0.004). Among patients with CD, fecal and serum ASCA levels were higher (Pâ=â0.01 and 0.01, respectively) in patients with more recently diagnosed disease. CONCLUSIONS: Fecal ASCA levels are higher in patients with active and newly diagnosed disease. Data from the present study suggest that measurement of fecal ASCA levels could represent a novel noninvasive biomarker for use in evaluating patients with suspected or known IBD. Further studies are necessary to better define the value of fecal ASCA measurements in identifying CD and response to therapy in children and young adults.
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Anticuerpos Antifúngicos/metabolismo , Enfermedad de Crohn/diagnóstico , Heces/química , Saccharomyces cerevisiae/inmunología , Adolescente , Biomarcadores/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Enfermedad de Crohn/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Curva ROC , Adulto JovenRESUMEN
The epithelial junction experiences mechanical force exerted by endogenous actomyosin activities and from interactions with neighboring cells. We hypothesize that tension generated at cell-cell adhesive contacts contributes to the maturation and assembly of the junctional complex. To test our hypothesis, we used a hydraulic apparatus that can apply mechanical force to intercellular junction in a confluent monolayer of cells. We found that mechanical force induces α-actinin-4 and actin accumulation at the cell junction in a time- and tension-dependent manner during junction development. Intercellular tension also induces α-actinin-4-dependent recruitment of vinculin to the cell junction. In addition, we have identified a tension-sensitive upstream regulator of α-actinin-4 as synaptopodin. Synaptopodin forms a complex containing α-actinin-4 and ß-catenin and interacts with myosin II, indicating that it can physically link adhesion molecules to the cellular contractile apparatus. Synaptopodin depletion prevents junctional accumulation of α-actinin-4, vinculin, and actin. Knockdown of synaptopodin and α-actinin-4 decreases the strength of cell-cell adhesion, reduces the monolayer permeability barrier, and compromises cellular contractility. Our findings underscore the complexity of junction development and implicate a control process via tension-induced sequential incorporation of junctional components.