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PURPOSE: To illuminate epidemiologic trends of maxillofacial trauma in an urban setting over an 11-year period. MATERIALS AND METHODS: We performed an exhaustive database search at the University of Pennsylvania. The data were collected from 11 years of attending oral and maxillofacial surgery clinician and resident operating room logs and was conducted from 2011 to 2021. The procedures where then selected for those that represented maxillofacial trauma. RESULTS: About 3,427 procedures met the inclusion and exclusion criteria to be considered a novel incidence of trauma. Dramatic differences in maxillofacial trauma exist between time of the year, patient age, and patient race. There is a correlation between summer time criminal activity and maxillofacial trauma. African-Americans ages 18 to 65 are the most affected patient demographic. CONCLUSIONS: With datasets of this size spanning over a decade, epidemiologic trends are able to be illuminated. There is a need for understanding the disparity between the demographics of the Philadelphia population and oral-maxillofacial (OM) trauma patients. A prospective extension of this study is to explore secondary, tertiary and quaternary ICD-10 codes to illuminate common injury patterns in OM trauma of varying patient populations.
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Traumatismos Maxilofaciales , Adolescente , Adulto , Anciano , Humanos , Incidencia , Traumatismos Maxilofaciales/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: Attempts to mitigate the coronavirus disease of 2019 (COVID) have disrupted the delivery of non-pandemic care. The purpose of this study was to evaluate the effects of the COVID pandemic on surgical volume and variety at an academic oral and maxillofacial surgery program. MATERIALS AND METHODS: A retrospective cohort study was conducted using the surgical logs of the University of Pennsylvania, Department of Oral and Maxillofacial Surgery from January 2012 through January 2021. Each record identified patient demographics and case classifications. The study predictor was timing of care, which was divided into pre-pandemic, peak pandemic, or post-peak pandemic. The primary study outcomes were the monthly procedure count and the procedure categories. The secondary dependent variables were patient age and race. Multivariate and univariate analyses of variance were used to determine whether pandemic effects existed within outcome groups. RESULTS: The final sample included 64,709 surgical procedures. Before, during, and after the pandemic peak, there were means of 691.0, 209.0, and 789.4 procedures per time period, respectively (P < .01). There was significantly more infection (baseline 2.2%, peak 6.0%, post-peak 2.0%, P < .01) and trauma (baseline 5.3%, peak 26.7%, post-peak 3.9%, P < .01) cases during the pandemic peak. The mean percentage of pediatric patients increased during the peak and post-peak periods (baseline 2.4%, peak 12.9%, post-peak 10.2%, P < .01). No differences were observed among the mean percentage of White (P = .12), Black (P = .21), and Hispanic (P = .25) patients treated. CONCLUSIONS: Along with a predictable decline in surgical numbers, a greater proportion of infection and trauma procedures were performed at the pandemic's peak. Despite these changes, surgery volume normalized and case variety returned to pre-pandemic levels in the post-peak period. Our study suggests that the addition of COVID restrictions did not change the case volume or variety in the months' after the initial crisis.
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COVID-19 , Cirugía Bucal , Niño , Humanos , Pandemias , Estudios Retrospectivos , SARS-CoV-2RESUMEN
PURPOSE: The purpose of this study was to analyze the effectiveness of the National Hockey League's (NHL) mandatory visor policy on the number and type of craniomaxillofacial (CMF) injuries. MATERIALS AND METHODS: A cross-sectional study was designed using the 2 databases: the NHL Injury Viz and the Pro Sports Transactions. CMF injuries and player characteristics from the NHL's 2009-2010 through the 2016-2017 seasons were obtained. The study outcomes of games missed and number of injuries were compared before and after the implementation of the league rule. RESULTS: A total of 149 CMF injuries were included in the final sample. Following the mandatory visor rule, there were significant decreases in the total number of CMF injuries per season (14.3 vs 30.7, P = .01) and the number of upper face injuries per season (7.0 vs 16.7, P = .04). Although there was no difference in the ratio of upper facial injuries before and after the rule change, players who wore a face shield did have a lower proportion of upper face injuries among all CMF injuries sustained (42.9 vs 64.6%, P < .01). Ultimately, neither face shield use (P = .49) nor implementing a mandatory face shield rule (P = .62) changed the number of games missed when injury did occur. CONCLUSIONS: Upper facial injuries were observed to be less common among players wearing face shields. After the NHL mandated face shields, there were significant decreases in the mean number of CMF and upper facial injuries per season. Face shields did not appear to influence the severity or downtime from injury that were sustained.
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Traumatismos en Atletas , Traumatismos Faciales , Hockey , Traumatismos en Atletas/epidemiología , Traumatismos en Atletas/prevención & control , Estudios Transversales , Traumatismos Faciales/epidemiología , Traumatismos Faciales/prevención & control , Humanos , IncidenciaRESUMEN
BACKGROUND: Substantial numbers of patients are now receiving either immunosuppressive therapies or chemotherapy. There are significant risks in such patients of developing opportunistic infections or re-activation of latent infections, with higher associated morbidity and mortality. The aim of this quality improvement project was to determine how effective 5 different specialties were in assessing and mitigating risks of developing opportunistic infections or re-activation of latent infections in patients undergoing immunosuppressive therapies. METHODS: This was a single centre audit where records of patients attending clinics providing immunosuppressive therapies were reviewed for the following: evidence of screening for blood-borne virus [BBV] infections, varicella and measles immunity, latent/active TB or hypogammaglobulinaemia, and whether appropriate vaccines had been advised or various infection risks discussed. These assessments were audited against both national and international guidelines, or a cross-specialty consensus guideline where specific recommendations were lacking. Two sub-populations were also analysed separately: patients receiving more potent immunosuppression and black and minority ethnic [BME] patients,. RESULTS: For the 204 patients fulfilling the inclusion criteria, BBV, varicella/measles and latent TB screening was inconsistent, as was advice for vaccinations, with few areas complying with specialty or consensus guidelines. Less than 10% of patients in one specialty were tested for HIV. In BME patients screening for HIV [60%], measles [0%] and varicella [40%] immunity and latent [30%] or active [20%] TB was low. Only 38% of patients receiving potent immunosuppression received Pneumocystis prophylaxis, with 3 of 4 specialties providing less than 15% of patients in this category with prophylaxis. CONCLUSIONS: Compliance with guidelines to mitigate risks of infection from immunosuppressive therapies was either inconsistent or poor for most specialties. New approaches to highlight such risks and assist appropriate pre-immunosuppression screening are needed.
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Enfermedades Transmisibles/diagnóstico , Adhesión a Directriz , Terapia de Inmunosupresión/efectos adversos , Adulto , Varicela/diagnóstico , Varicela/prevención & control , Control de Enfermedades Transmisibles , Enfermedades Transmisibles/etiología , Inglaterra , Femenino , Hospitales/estadística & datos numéricos , Humanos , Huésped Inmunocomprometido , Inmunosupresores , Masculino , Sarampión/diagnóstico , Sarampión/prevención & control , Persona de Mediana Edad , Neumonía por Pneumocystis/diagnóstico por imagen , Neumonía por Pneumocystis/prevención & control , Estudios Retrospectivos , Vacunación , Virosis/diagnóstico , Virosis/prevención & controlRESUMEN
Methicillin-resistant Staphylococcus aureus is a 'superbug' that is responsible for extensive death and morbidity. Chronic S. aureus infections are associated with the presence of intracellular bacteria and the host cytosol is an aerobic low-redox-potential (Eh) environment. How S. aureus adapts to aerobic low-Eh environments is understudied. A low external Eh, imposed by the non-metabolizable reductant dithiothreitol, resulted in transcriptional reprogramming mediated by the redox-responsive transcription factors AgrA, Rex and SrrBA, resulting in a shift towards fermentative metabolism. Accordingly, in the presence of the host cytoplasmic reductant glutathione, the aerobic respiration of S. aureus was impaired, the intracellular NADH:NAD+ ratio increased, lactate dehydrogenase was induced, resistance to the aminoglycoside antibiotic gentamicin was enhanced and greater numbers of small-colony variants (SCVs) were detected. These observations suggest that entry of S. aureus into the aerobic low-Eh environment of the host cytosol could result in adaptive responses that promote the formation of SCVs.
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Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/fisiología , Adaptación Biológica , Aerobiosis , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Citoplasma/química , Citoplasma/microbiología , Regulación Bacteriana de la Expresión Génica , Humanos , Oxidación-Reducción , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
The organ of Corti, located within the mammalian cochlea, contains a precise mosaic of hair cells (HC) and supporting cells (SC), the patterning of which is critical for auditory function. Progenitors of HCs and SCs are found in the same post-mitotic region of the cochlear duct during early stages of cochlear development, and both HCs and SCs are absent in mice lacking the transcription factor Atoh1. Based on existing data, Atoh1 is thought to be the earliest determinant of HC fate, and to have a cell-autonomous role in HC differentiation, but the lineage of Atoh1-positive cells within the cochlear duct remains unclear. To address this issue, we used an inducible Atoh1(CreâPR) allele to permanently mark Atoh1-expressing cells at different developmental time points. We found that up to 30% of cells from the Atoh1-lineage develop as SCs, and that the number of Atoh1-positive SCs decreases both spatially and temporally in a pattern consistent with ongoing commitment. Modulation of Notch signaling, necessary for formation of the HC-SC mosaic, changes the percentage of cells from the Atoh1-lineage that develop as either HCs or SCs. The HC-SC ratio is also affected by morphogenesis of the cochlea, as inhibiting the outgrowth of the cochlear duct increases the number of Atoh1-lineage cells that develop as SCs. Our results demonstrate that the Atoh1-lineage is established early in cochlear development, but also show that expression of Atoh1 does not absolutely result in commitment to a HC fate.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular/fisiología , Cóclea/embriología , Regulación del Desarrollo de la Expresión Génica/fisiología , Células Ciliadas Auditivas/citología , Células Laberínticas de Soporte/citología , Factores de Edad , Análisis de Varianza , Animales , Cóclea/citología , Perfilación de la Expresión Génica , Células Ciliadas Auditivas/metabolismo , Inmunohistoquímica , Células Laberínticas de Soporte/metabolismo , Ratones , Receptores Notch/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Aplasia cutis congenita (ACC) is a rare connective tissue disorder that affects the epidermis, dermis, and subcutaneous tissue. Lesions can be small and benign or, in some cases, large and extensive. The lesions can be covered by a thin membrane, and depending on their location, they can make the underlying tissue vulnerable to damage or infection. This case report focuses on a term male infant born with extensive scalp defects and later diagnosed with ACC. The study will discuss the pathophysiology and classification of this disorder. This will provide clinicians with a recommended approach for the initial management of infants diagnosed with ACC in their practice.
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Ethanol is a powerful substance and, when consumed during pregnancy, has significant psychoactive and developmental effects on the developing fetus. These abnormalities include growth retardation, neurological deficits, and behavioral and cognitive deficiencies, commonly referred to as fetal alcohol spectrum disorder. The effect of ethanol has been reported to affect cellular development on the embryonic level, however, not much is known about mutations contributing to the influence of ethanol. The purpose of our study was to determine if mutation contribute to changes in differentiation patterning, cell-cycle regulatory gene expression, and DNA methylation in human embryonic stem cells after ethanol exposure. We exposed human embryonic stem cells (with and without know DNA mutations) to a low concentration (20 mM) of ethanol and measured neurosphere proliferation and differentiation, glial protein levels, expression of various cell-cycle genes, and DNA methylation. Ethanol altered cell-cycle gene expression between the two cell lines; however, gene methylation was not affected in ether lines.
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Diferenciación Celular/efectos de los fármacos , Aberraciones Cromosómicas , Células Madre Embrionarias/efectos de los fármacos , Etanol/toxicidad , Neuronas/patología , Esferoides Celulares/efectos de los fármacos , Bromodesoxiuridina/metabolismo , Recuento de Células , Línea Celular , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Células Madre Embrionarias/citología , Células Madre Embrionarias/patología , Fase G2/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Indoles/metabolismo , Mitosis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Esferoides Celulares/citología , Esferoides Celulares/patologíaRESUMEN
Aspirin demonstrated a significantly higher rate of postoperative venous thromboembolic events compared with enoxaparin in this noninferiority study.
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Heparina de Bajo-Peso-Molecular , Tromboembolia Venosa , Humanos , Heparina de Bajo-Peso-Molecular/uso terapéutico , Aspirina/uso terapéutico , Anticoagulantes/uso terapéutico , Tromboembolia Venosa/prevención & control , Tromboembolia Venosa/tratamiento farmacológico , Enoxaparina/uso terapéutico , HeparinaRESUMEN
Efforts to develop a range of HIV prevention products that can serve as behaviorally congruent viable alternatives to consistent condom use and oral pre-exposure prophylaxis (PrEP) remain crucial. MTN-035 was a randomized crossover trial seeking to evaluate the safety, acceptability, and adherence to three placebo modalities (insert, suppository, enema) prior to receptive anal intercourse (RAI). If participants had no RAI in a week, they were asked to use their assigned product without sex. We hypothesized that the modalities would be acceptable and safe for use prior to RAI, and that participants would report high adherence given their behavioral congruence with cleansing practices (e.g., douches and/or enemas) and their existing use to deliver medications (e.g., suppositories; fast-dissolving inserts) via the rectum. Participants (N = 217) were sexual and gender minorities enrolled in five different countries (Malawi, Peru, South Africa, Thailand, and the United States of America). Mean age was 24.9 years (range 18-35 years). 204 adverse events were reported by 98 participants (45.2%); 37 (18.1%) were deemed related to the study products. The proportion of participants reporting "high acceptability" was 72% (95%CI: 65% - 78%) for inserts, 66% (95%CI: 59% - 73%) for suppositories, and 73% (95%CI: 66% - 79%) for enemas. The proportion of participants reporting fully adherent per protocol (i.e., at least one use per week) was 75% (95%CI: 69% - 81%) for inserts, 74% (95%CI: 68% - 80%) for suppositories, and 83% (95%CI: 77% - 88%) for enemas. Participants fully adherent per RAI-act was similar among the three products: insert (n = 99; 58.9%), suppository (n = 101; 58.0%) and enema (n = 107; 58.8%). The efficacy and effectiveness of emerging HIV prevention drug depends on safe and acceptable delivery modalities that are easy to use consistently. Our findings demonstrate the safety and acceptability of, and adherence to, enemas, inserts, and suppositories as potential modalities through which to deliver a rectal microbicide.
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Antiinfecciosos , Infecciones por VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Masculino , Humanos , Adolescente , Adulto Joven , Adulto , Recto , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Homosexualidad Masculina , Supositorios , Conducta Sexual , Antiinfecciosos/uso terapéuticoRESUMEN
Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generated single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. Seventy-five percent of elements (44 of 59) validated in an in vivo transgenic reporter assay, demonstrating that single cell accessibility is a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieved significant reduction in our variant search space and nominated candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as new candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work provides novel non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.
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Hindbrain networks important for sensation and arousal contain diverse neuronal populations with distinct projections, yet share specific characteristics such as neurotransmitter expression. The relationship between the function of these neurons, their developmental origin, and the timing of their migration remains unclear. Mice lacking the proneural transcription factor Math1 (Atoh1) lose neurons essential for hearing, balance, and unconscious proprioception. By using a new, inducible Math1(Cre*PR) allele, we found that Math1 is also required for the conscious proprioceptive system, including excitatory projection neurons of the dorsal column nuclei and for vital components of the interoceptive system, such as Barrington's nucleus, that is closely associated with arousal. In addition to specific networks, Math1 lineages shared specific neurotransmitter expression, including glutamate, acetylcholine, somatostatin, corticotropin releasing hormone, and nitric oxide. These findings identify twenty novel Math1 lineages and indicate that the Math1 network functions partly as an interface for conscious (early-born) and unconscious (late-born) proprioceptive inputs to the cortex and cerebellum, respectively. In addition, these data provide previously unsuspected genetic and developmental links between proprioception, interoception, hearing, and arousal.
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Nivel de Alerta/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Propiocepción/fisiología , Rombencéfalo/fisiología , Acetilcolina/metabolismo , Animales , Vías Auditivas/embriología , Vías Auditivas/fisiología , Percepción Auditiva/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Hormona Liberadora de Corticotropina/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Ácido Glutámico/metabolismo , Levodopa/metabolismo , Ratones , Ratones Transgénicos , Red Nerviosa/embriología , Red Nerviosa/fisiología , Vías Nerviosas/embriología , Vías Nerviosas/fisiología , Neuronas/fisiología , Óxido Nítrico/metabolismo , Embarazo , Rombencéfalo/embriología , Somatostatina/metabolismoRESUMEN
Most fish excrete their nitrogenous waste across the gills as ammonia through the activity of the Rhesus glycoprotein ammonium transporters. In contrast, fish of the subgenus Alcolapia (Oreochromis) are the only vertebrates that survive the extreme conditions of the soda lakes of Natron and Magadi in East Africa and have evolved adaptations to the highly alkaline waters including the ability to excrete their nitrogenous waste as urea. Nevertheless, Alcolapia retain the Rhesus glycoprotein genes in their genomes and using two heterologous expression systems, we demonstrate that Alcolapia Rhbg is capable of moving ammonia. Comparing ammonia and urea excretion from two closely related Alcolapia species from the same aquarium, we found that while Alcolapia grahami remains fully ureotelic after many generations in lab conditions, Alcolapia alcalica excretes some of its nitrogenous waste as ammonia. Using in situ hybridisation, we demonstrate robust, localised gene expression of Rhbg, rhcg1 and rhcg2 in the gill tissue in both A. alcalica embryos and adults, similar to that in other ammoniotelic fish. In contrast, the expression of these genes in A. grahami gills is much lower than in A. alcalica, suggesting the rapid evolution of a molecular mechanism underlying the complete ureotelism of A. grahami.
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Compuestos de Amonio , Branquias , Animales , Branquias/metabolismo , Amoníaco/metabolismo , Compuestos de Amonio/metabolismo , Peces/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Urea/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismoAsunto(s)
Neoplasias de la Coroides/patología , Cuerpo Ciliar/patología , Tumores Neuroectodérmicos Primitivos/patología , Neoplasias de la Úvea/patología , Adulto , Biomarcadores de Tumor/metabolismo , Neoplasias de la Coroides/diagnóstico por imagen , Neoplasias de la Coroides/metabolismo , Cuerpo Ciliar/diagnóstico por imagen , Diagnóstico Diferencial , Enucleación del Ojo , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Tumores Neuroectodérmicos Primitivos/diagnóstico por imagen , Tumores Neuroectodérmicos Primitivos/metabolismo , Ultrasonografía , Neoplasias de la Úvea/diagnóstico por imagen , Neoplasias de la Úvea/metabolismoRESUMEN
Body odour is a characteristic trait of Homo sapiens, however its role in human behaviour and evolution is poorly understood. Remarkably, body odour is linked to the presence of a few species of commensal microbes. Herein we discover a bacterial enzyme, limited to odour-forming staphylococci that are able to cleave odourless precursors of thioalcohols, the most pungent components of body odour. We demonstrated using phylogenetics, biochemistry and structural biology that this cysteine-thiol lyase (C-T lyase) is a PLP-dependent enzyme that moved horizontally into a unique monophyletic group of odour-forming staphylococci about 60 million years ago, and has subsequently tailored its enzymatic function to human-derived thioalcohol precursors. Significantly, transfer of this enzyme alone to non-odour producing staphylococci confers odour production, demonstrating that this C-T lyase is both necessary and sufficient for thioalcohol formation. The structure of the C-T lyase compared to that of other related enzymes reveals how the adaptation to thioalcohol precursors has evolved through changes in the binding site to create a constrained hydrophobic pocket that is selective for branched aliphatic thioalcohol ligands. The ancestral acquisition of this enzyme, and the subsequent evolution of the specificity for thioalcohol precursors implies that body odour production in humans is an ancient process.
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Alcoholes/metabolismo , Cuerpo Humano , Odorantes/análisis , Compuestos de Sulfhidrilo/metabolismo , Alcoholes/química , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Teorema de Bayes , Sitios de Unión , Liasas de Carbono-Azufre/química , Liasas de Carbono-Azufre/metabolismo , Cisteína/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Modelos Moleculares , Filogenia , Staphylococcus/metabolismo , Compuestos de Sulfhidrilo/química , Factores de TiempoRESUMEN
The rhombic lip (RL) is an embryonic proliferative neuroepithelium that generates several groups of hindbrain neurons. However, the precise boundaries and derivatives of the RL have never been genetically identified. We use beta-galactosidase expressed from the Math1 locus in Math1-heterozygous and Math1-null mice to track RL-derived cells and to evaluate their developmental requirements for Math1. We uncover a Math1-dependent rostral rhombic-lip migratory stream (RLS) that generates some neurons of the parabrachial, lateral lemniscal, and deep cerebellar nuclei, in addition to cerebellar granule neurons. A more caudal Math1-dependent cochlear extramural stream (CES) generates the ventral cochlear nucleus and cochlear granule neurons. Similarly, mossy-fiber precerebellar nuclei require Math1, whereas the inferior olive and locus coeruleus do not. We propose that Math1 expression delimits the extent of the rhombic lip and is required for the generation of the hindbrain superficial migratory streams, all of which contribute neurons to the proprioceptive/vestibular/auditory sensory network.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Tronco Encefálico , Cerebelo , Desarrollo Embrionario/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Neuronas/fisiología , Factores de Edad , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Western Blotting/métodos , Tronco Encefálico/citología , Tronco Encefálico/embriología , Tronco Encefálico/metabolismo , Movimiento Celular/fisiología , Cerebelo/citología , Cerebelo/embriología , Cerebelo/metabolismo , Cóclea/citología , Cóclea/embriología , Cóclea/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Embrión de Mamíferos , Glicósido Hidrolasas/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Proteínas con Homeodominio LIM , Operón Lac/fisiología , Ratones , Ratones Noqueados , Modelos Biológicos , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Proteínas de Dominio T Box , Factores de TranscripciónRESUMEN
In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.
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Esclerosis Amiotrófica Lateral/genética , Glicoproteínas de Membrana/genética , Neuronas Motoras/metabolismo , Neuronas Eferentes/metabolismo , Proteínas de Complejo Poro Nuclear/genética , Superóxido Dismutasa-1/genética , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/terapia , Animales , Diferenciación Celular/genética , Nervios Craneales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Neuronas Motoras/patología , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/metabolismo , Neuronas Eferentes/efectos de los fármacos , Médula Espinal/crecimiento & desarrollo , Médula Espinal/patologíaRESUMEN
Unipolar brush cells (UBCs) are glutamatergic interneurons in the cerebellar cortex and dorsal cochlear nucleus. We studied the development of UBCs, using transcription factor Tbr2/Eomes as a marker for UBCs and their progenitors in embryonic and postnatal mouse cerebellum. Tbr2+ UBCs appeared to migrate out of the upper rhombic lip via two cellular streams: a dorsal pathway into developing cerebellar white matter, where the migrating cells dispersed widely before entering the internal granular layer, and a rostral pathway along the cerebellar ventricular zone toward the brainstem. Ablation of the rhombic lip in organotypic slice cultures substantially reduced the production of Tbr2+ UBCs. In coculture experiments, Tbr2+ UBCs migrated from rhombic lip explants directly into the developing white matter of adjacent cerebellar slices. The origin of Tbr2+ UBCs was confirmed by colocalization with beta-galactosidase expressed from the Math1 locus, a molecular marker of rhombic lip lineages. Moreover, the production of Tbr2+ UBCs was Math1 dependent, as Tbr2+ UBCs were severely reduced in Math1-null cerebellum. In reeler mutant mice, Tbr2+ UBCs accumulated near the rhombic lip, consistent with impaired migration through developing white matter. Our results suggest that UBCs arise from the rhombic lip and migrate via novel pathways to their final destinations in the cerebellum and dorsal cochlear nucleus. Our findings support a model of cerebellar neurogenesis, in which glutamatergic and GABAergic neurons are produced from separate progenitor pools located mainly in the rhombic lip and the cerebellar ventricular zone, respectively.
Asunto(s)
Cerebelo/embriología , Cerebelo/fisiología , Interneuronas/citología , Interneuronas/fisiología , Fibras Nerviosas Mielínicas/ultraestructura , Rombencéfalo/embriología , Rombencéfalo/fisiología , Animales , Diferenciación Celular , Movimiento Celular/fisiología , Células Cultivadas , Cerebelo/citología , Ratones , Ratones Mutantes Neurológicos , Fibras Nerviosas Mielínicas/fisiología , Rombencéfalo/citologíaRESUMEN
The Florence Nightingale Foundation (FNF) is a charity that awards scholarships in leadership, travel and research to nurses, midwives and other healthcare professionals to promote excellence in practice. The FNF offers mentoring support to scholars, and provides support with career development and writing articles for publication, in addition to the financial award. The leadership scholarships are bespoke: leadership scholars can access a range of development opportunities that are specially commissioned for them, and select their programme of study and experiences, based on their individual needs. All scholarships provide opportunities to represent the FNF and to meet other scholars at the FNF annual conference. This article provides an overview of the FNF scholarships, based on the findings of two evaluations that demonstrated the value of these scholarships in improving services for patients and carers, as well as enhancing the careers of individual scholars.
RESUMEN
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymkinsT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.