RESUMO
The ocular surface epithelia, including the stratified but non-keratinized corneal, limbal and conjunctival epithelium, in concert with the epidermal keratinized eyelid epithelium, function together to maintain eye health and vision. Abnormalities in cellular proliferation or differentiation in any of these surface epithelia are central in the pathogenesis of many ocular surface disorders. Goblet cells are important secretory cell components of various epithelia, including the conjunctiva; however, mechanisms that regulate goblet cell differentiation in the conjunctiva are not well understood. Herein, we report that conditional deletion of transforming growth factor ß receptor II (Tgfbr2) in keratin 14-positive stratified epithelia causes ocular surface epithelial hyperplasia and conjunctival goblet cell expansion that invaginates into the subconjunctival stroma in the mouse eye. We found that, in the absence of an external phenotype, the ocular surface epithelium develops properly, but young mice displayed conjunctival goblet cell expansion, demonstrating that TGFß signaling is required for normal restriction of goblet cells within the conjunctiva. We observed increased expression of SAM-pointed domain containing ETS transcription factor (SPDEF) in stratified conjunctival epithelial cells in Tgfbr2 cKO mice, suggesting that TGFß restricted goblet cell differentiation directly by repressing Spdef transcription. Gain of function of Spdef in keratin 14-positive epithelia resulted in the ectopic formation of goblet cells in the eyelid and peripheral cornea in adult mice. We found that Smad3 bound two distinct sites on the Spdef promoter and that treatment of keratin 14-positive cells with TGFß inhibited SPDEF activation, thereby identifying a novel mechanistic role for TGFß in regulating goblet cell differentiation.
Assuntos
Diferenciação Celular/fisiologia , Túnica Conjuntiva/crescimento & desenvolvimento , Células Caliciformes/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Imunoprecipitação da Cromatina , Túnica Conjuntiva/citologia , Citometria de Fluxo , Técnicas Histológicas , Queratina-14/metabolismo , Microdissecção e Captura a Laser , Luciferases , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteína Smad3/metabolismoRESUMO
Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-ß has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGFß-dependent pathology have not been segregated. Here, we generated transgenic mice with myofiber-specific inhibition of TGFß signaling owing to expression of a TGFß type II receptor dominant-negative (dnTGFßRII) truncation mutant. Expression of dnTGFßRII in myofibers mitigated the dystrophic phenotype observed in δ-sarcoglycan-null (Sgcd(-/-)) mice through a mechanism involving reduced myofiber membrane fragility. The dnTGFßRII transgene also reduced muscle injury and improved muscle regeneration after cardiotoxin injury, as well as increased satellite cell numbers and activity. An unbiased global expression analysis revealed a number of potential mechanisms for dnTGFßRII-mediated protection, one of which was induction of the antioxidant protein metallothionein (Mt). Indeed, TGFß directly inhibited Mt gene expression in vitro, the dnTGFßRII transgene conferred protection against reactive oxygen species accumulation in dystrophic muscle and treatment with Mt mimetics protected skeletal muscle upon injury in vivo and improved the membrane stability of dystrophic myofibers. Hence, our results show that the myofibers are central mediators of the deleterious effects associated with TGFß signaling in MD.
Assuntos
Distrofias Musculares/genética , Miofibrilas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/patologia , Proteínas Cardiotóxicas de Elapídeos/farmacologia , Crotoxina/farmacologia , Modelos Animais de Doenças , Combinação de Medicamentos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Metalotioneína/genética , Metalotioneína/metabolismo , Camundongos , Camundongos Transgênicos , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Mutação , Miofibrilas/efeitos dos fármacos , Miofibrilas/patologia , Proteínas Serina-Treonina Quinases/deficiência , Espécies Reativas de Oxigênio/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Sarcoglicanas/deficiência , Sarcoglicanas/genética , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Células Satélites de Músculo Esquelético/metabolismo , Células Satélites de Músculo Esquelético/patologia , Fator de Crescimento Transformador beta/farmacologia , TransgenesRESUMO
INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) has been available since the 1980s. Routine replacement is conducted at bedside with relatively few complications. Two replacement methods have come into practice: the percutaneous method and the endoscopic method. The laparoscopic method has recently become favorable in the pediatric population. PRESENTATION OF CASE: Herein, we describe a situation in which a gastrostomy tube was replaced at bedside on a patient with previous head and neck surgery for lingual cancer. The percutaneous traction method was used, and gastrostomy tube replacement into the gastric lumen could not be confirmed on subsequent imaging. The patient was ultimately taken to surgery for an open procedure where it was discovered that initial PEG placement had traversed the small bowel mesentery en route to the gastric lumen. DISCUSSION: The PEG tube is not a permanent device and routine exchange every 6-12 months is recommended. The percutaneous method and endoscopic method for gastrostomy tube replacement have both been used routinely, each with their set of complications. A third technique, laparoscopic placement, is the preferred modality in the pediatric population. Advantages are twofold: direct visualization of the stomach, thus eliminating inadvertent hollow viscus injury, and applicability in infants too small to undergo endoscopy necessary for PEG tube placement. CONCLUSION: Consideration for laparoscopic placement or replacement in the head and neck cancer patient population, in which interval endoscopy is impossible, is thus advocated.
RESUMO
Women represent only 15.3% of all residents and fellows in the field of orthopedic surgery. The rate of increase of women in the field of orthopedics continues to lag behind all other surgical specialties. The purpose of this study was 2-fold: (1) to evaluate male/female representation in orthopedic specialty societies and (2) to examine the involvement of male/female orthopedic surgeons on committees, in leadership roles, at annual meetings, and in receipt of monetary awards. A 12-question, anonymous survey was distributed to the executive directors of all 23 orthopedic specialty societies. The survey included questions about the breakdown of male/female membership as well as male/female orthopedic surgeon participation in various functions of the society. Fourteen (60.9%) of 23 executive directors from orthopedic specialty societies responded to the survey. Seven (50.0%) of 14 survey respondents reported society membership of more than 1000. Six (42.9%) of 14 survey respondents reported male membership of more than 1000, while only the Ruth Jackson Orthopaedic Society reported female membership of more than 1000. Eleven (78.6%) of 14 survey respondents (eg, American Association of Hip and Knee Surgeons, American Orthopaedic Foot and Ankle Society, American Orthopaedic Society for Sports Medicine) reported having more than 10 men in leadership positions, whereas 13 (92.9%) of 14 respondents reported 10 or fewer women in leadership positions. Most orthopedic specialty societies have lower female than male membership, fewer women in leadership positions, and fewer monetary awards granted to women compared with men. This disparity was more evident in anatomic societies (eg, American Association of Hip & Knee Surgeons, American Orthopaedic Foot and Ankle Society) compared with general orthopedic societies (eg, Ruth Jackson Orthopaedic Society, Orthopaedic Research Society). Female orthopedic surgeons remain underrepresented in orthopedic specialty societies. [Orthopedics. 2021;44(5):289-292.].
Assuntos
Cirurgiões Ortopédicos , Ortopedia , Médicas , Cirurgiões , Feminino , Humanos , Liderança , Masculino , Sociedades Médicas , Estados UnidosRESUMO
The major impediment to increased human papillomavirus (HPV) vaccination coverage in young males and females is lack of health care provider recommendation. Despite its efficacy in preventing cervical cancer, HPV vaccination in females (49.5%) and males (37.5%) ages 13 through 17 falls well below the Centers for Disease Control and Prevention's (CDC) Healthy People 2020 target of 80% coverage. Parents' willingness to vaccinate their child has been shown to be much higher when physicians share personal vaccination decisions for their own children as well as what other parents have done at that particular clinic. Furthermore, the vaccine must be presented presumptively as a "bundle" along with the rest of the standard adolescent vaccine panel. Multiple exemplars presented including in several European countries, low-income countries and Rwanda, demonstrate that school-based health care systems dramatically increase vaccination coverage. Finally, acceptability for vaccination of males must improve by increasing provider recommendation and by presenting the HPV vaccine as a penile, anal and oropharyngeal cancer prevention therapy in males and not merely a vaccine to prevent cervical cancers in females. Paediatricians, obstetrician/gynaecologists and primary care physicians should consider these data as a call-to-action. Key messages ⢠Despite recent efforts in the US, only 49.5% of females and only 37.5% of males ages 13 through 17 have received all recommended HPV vaccine doses. These numbers fall well below the 80% target set forth by the Healthy People 2020 initiative. ⢠According to the CDC, if health care providers increase HPV vaccination rates in eligible recipients to 80%, it is estimated that an additional 53,000 cases of cervical cancer could be prevented during the lifetime of those younger than 12 years. Furthermore, for every year that the vaccination rate does not increase, an additional 4400 women will develop cervical cancer. ⢠First and foremost, healthcare providers (HCPs) must make a strong recommendation to vaccinate patients and these recommendations must become routine, including for males. ⢠It is clear that HPV vaccination rates improve significantly when vaccine administration occurs at designated, well-organized sites such as school-based vaccination programmes. Furthermore, HPV vaccination should be a high school requirement and offered in the standard adolescent vaccine panel as a bundle with Tdap and MenACWY vaccines in order to promote maximum adherence. ⢠Finally, research on immunogenicity and antibody titre longevity needs to be done in newborns. The HPV vaccine may be recommended in the newborn panel of vaccines to avoid any issues of sexualization and misplaced fears of sexual disinhibition, akin to the success of the Hepatitis B vaccine in the 1980s. ⢠The HPV vaccine is a vaccine against cancer and should be aggressively marketed as such. As healthcare providers, we need to make every effort to overcome barriers, real or perceived, to protecting our population from potential morbidity and mortality associated with this virus.
Assuntos
Vacinação em Massa/estatística & dados numéricos , Neoplasias/prevenção & controle , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Cobertura Vacinal/estatística & dados numéricos , Promoção da Saúde/métodos , Humanos , Marketing de Serviços de Saúde/métodos , Vacinação em Massa/tendências , Neoplasias/virologia , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Cobertura Vacinal/tendênciasRESUMO
Primary cilia are nearly ubiquitous, cellular projections that function to transduce molecular signals during development. Loss of functional primary cilia has a particularly profound effect on the developing craniofacial complex, causing several anomalies including craniosynostosis, micrognathia, midfacial dysplasia, cleft lip/palate and oral/dental defects. Development of the craniofacial complex is an intricate process that requires interactions between several different tissues including neural crest cells, neuroectoderm and surface ectoderm. To understand the tissue-specific requirements for primary cilia during craniofacial development we conditionally deleted three separate intraflagellar transport genes, Kif3a, Ift88 and Ttc21b with three distinct drivers, Wnt1-Cre, Crect and AP2-Cre which drive recombination in neural crest, surface ectoderm alone, and neural crest, surface ectoderm and neuroectoderm, respectively. We found that tissue-specific conditional loss of ciliary genes with different functions produces profoundly different facial phenotypes. Furthermore, analysis of basic cellular behaviors in these mutants suggests that loss of primary cilia in a distinct tissue has unique effects on development of adjacent tissues. Together, these data suggest specific spatiotemporal roles for intraflagellar transport genes and the primary cilium during craniofacial development.
Assuntos
Anormalidades Craniofaciais/genética , Face/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Crânio/embriologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Cílios/genética , Face/anormalidades , Feminino , Deleção de Genes , Cinesinas/genética , Masculino , Camundongos , Crista Neural/embriologia , Crista Neural/metabolismo , Placa Neural/embriologia , Placa Neural/metabolismo , Crânio/anormalidades , Crânio/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
Primary cilia are cell surface, microtubule-based organelles that dynamically extend from cells to receive and process molecular and mechanical signaling cues. In the last decade, this organelle has gained increasing popularity due to its ability to act as a cellular antenna, receive molecular stimuli, and respond to the cell's environment. A growing field of data suggests that various tissues utilize and interpret the loss of cilia in different ways. Thus, careful examination of the role of cilia on individual cell types and tissues is necessary. Neural crest cells (NCCs) are an excellent example of cells that survey their environment for developmental cues. In this review, we discuss how NCCs utilize primary cilia during their ontogenic development, paying special attention to the role primary cilia play in processing developmental signals required for NCC specification, migration, proliferation, and differentiation. We also discuss how the loss of functional cilia on cranial and trunk NCCs affects the development of various organ systems to which they contribute. A deeper understanding of ciliary function could contribute greatly to understanding the molecular mechanisms guiding NCC development and differentiation. Furthermore, superimposing the ciliary contribution on our current understanding of NCC development identifies new avenues for therapeutic intervention in neurocristopathies.