RESUMO
BACKGROUND: Ethanol ablation for the treatment of thyroid cysts has been well documented in the literature as a safe, effective treatment option in the elective setting. This study demonstrates the use of ethanol ablation in the emergency setting. METHODS: Three patients presenting with airway-threatening compressive symptoms secondary to a thyroid cyst were treated with ethanol ablation within 24 hours of presentation to hospital. RESULTS: All patients had symptom resolution at a median of nine months follow up post procedure. Sixty-six per cent of patients required only one treatment. There was a median of 100 per cent radiological resolution of the cystic component. The median Glasgow Benefit Inventory score was +27.7, similar to that for tonsillectomy. CONCLUSION: Ethanol ablation is a safe, cost-effective and efficient treatment option for thyroid cysts in the acute setting.
Assuntos
Cistos , Neoplasias da Glândula Tireoide , Humanos , Etanol/uso terapêutico , Cistos/cirurgia , Resultado do TratamentoRESUMO
Transcatheter aortic valve replacement (TAVR) offers well established benefit for adults with severe aortic stenosis, although applications in the pediatric population remain limited. We describe a case of a 15-year-old male with complex congenital heart disease presenting with cardiogenic shock in the setting of mixed severe aortic stenosis (AS) and severe aortic insufficiency (AI). Self-expanding TAVR was performed via suprasternal approach with robust clinical improvement. At one month follow up, he had resolution of clinical heart failure with improvement in ejection fraction and no symptoms of valvulopathy. To our knowledge, there have been no described cases of suprasternal TAVR in a pediatric patient.
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Próteses Valvulares Cardíacas , Substituição da Valva Aórtica Transcateter , Adolescente , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Criança , Humanos , Masculino , Fatores de Risco , Choque Cardiogênico , Resultado do TratamentoRESUMO
INTRODUCTION: Heterotaxy syndrome presents a unique challenge in surgical management, even in the current era. We hypothesized that certain anatomic subsets merit novel strategies. METHODS: We analyzed morphologic details, surgeries, comorbidities, subsequent admissions, and survival using Kaplan-Meier methods and multivariable risk models from a single-institution experience of 103 consecutive patients with heterotaxy who underwent cardiac surgery between January 1, 1990, and May 31, 2016. RESULTS: Of the 103 patients (50 males and 53 females), 31 had left atrial isomerism, 64 had right atrial isomerism (RAI), and 8 patients' isomerism was indeterminate (IND), with first cardiac operation at a mean 1.0 year (standard deviation ±3.0 years) of age. Kaplan-Meier overall survival estimate was 83.1% at six months, 77.8% at one year, 65.9% at five years, and 52.1% at ten years. Survival was particularly low among RAI following repair of total anomalous pulmonary venous connection (TAPVC) at first operation, with one- and five-year survival of 57% and 46%, respectively. By multivariable analysis, the only risk factor for death during the early phase (hazard model) was repair of TAPVC at the first cardiac operation (hazard ratio [HR]: 4.4, P = .01), and risk factors during the longer term constant phase were atrioventricular valve (AVV) regurgitation (HR: 4.2, P < .01), male gender (HR: 3.7, P < .01), and two-ventricle repair (HR: 3.0, P = .02). Patients with heterotaxy undergoing the Fontan procedure had excellent subsequent survival (85% at ten years). CONCLUSIONS: This analysis of over 100 patients with heterotaxy identified TAPVC requiring initial repair as the major risk factor for early death and important AVV regurgitation as the major risk factor in the longer term. Survival with RAI and early repair of TAPVC were poor, with one-year mortality exceeding 40%. Patients with single ventricle completing the Fontan operation enjoyed outstanding ten-year survival (85%). Initial management of RAI requiring early repair of TAPVC remains challenging. For this high-risk subset, alternative strategies such as early referral for cardiac transplantation evaluation warrant consideration.
Assuntos
Síndrome de Heterotaxia/cirurgia , Síndrome de Cimitarra/cirurgia , Criança , Pré-Escolar , Feminino , Técnica de Fontan , Ventrículos do Coração/cirurgia , Síndrome de Heterotaxia/complicações , Síndrome de Heterotaxia/mortalidade , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Síndrome de Cimitarra/complicações , Síndrome de Cimitarra/mortalidade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Hematophagous arthropod bloodmeal identification has remained a challenge in the field of vector biology, but these studies are important to understand blood feeding patterns of arthropods, spatial, and temporal patterns in arbovirus transmission cycles, and risk of human and veterinary disease. We investigated the use of an existing vertebrate primer set for use on the droplet digital polymerase chain reaction (ddPCR) platform, to explore the use of this technology in the identification and quantification of vertebrate DNA in mosquito blood meals. Host DNA was detectable 48-h post-engorgement in some mosquitoes by ddPCR, compared with 24-h post-engorgement using traditional PCR. The capability of ddPCR for absolute quantification of template DNA offers unique potential applications of this new technology to field studies on the ecology of vector-borne diseases, but currently with limited scope.
Assuntos
Culicidae/química , DNA/análise , Animais , Bovinos , Reação em Cadeia da PolimeraseRESUMO
Infants of diabetic mothers are at risk for transient hypertrophic cardiomyopathy. These infants are typically asymptomatic, but may develop signs of poor cardiac output from left ventricular outflow tract obstruction. This case illustrates the successful use of extracorporeal membrane oxygenation to support cardiac output in an infant of a diabetic mother with outflow tract obstruction until hypertrophy improved.
Assuntos
Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/terapia , Oxigenação por Membrana Extracorpórea , Obstrução do Fluxo Ventricular Externo/diagnóstico por imagem , Obstrução do Fluxo Ventricular Externo/fisiopatologia , Adulto , Débito Cardíaco , Diabetes Mellitus , Ecocardiografia , Feminino , Humanos , Recém-Nascido , Masculino , Mães , Gravidez , Gravidez em DiabéticasRESUMO
BACKGROUND: Spinal cord stimulation (SCS) is now established as the primary treatment for failed back surgery syndrome (FBSS). Commonly, patients with chronic pain and FBSS often report symptoms of anxiety and depression resulting from this condition. These factors can modulate and amplify the pain experience, therefore, further challenging treatment success. AIMS: This study examined the efficacy of SCS on alleviating the symptoms of anxiety and depression associated with chronic pain as well as pain intensity in a group of patients with FBSS. METHODS: A convenience sample (n = 26) was selected for participation. Questionnaires [Hospital Anxiety and Depression Scale (HADS) and Brief Pain Inventory Short Form (BPI-SF)] were completed and examined pre and post spinal cord implant. RESULTS: Analysis of the data 1 year following SCS indicates that there was a statistical significant improvement in the symptoms of depression and anxiety reported as well as pain intensity in all participants (p < 0.001). Both anxiety and depression scores on the HADS were significantly lower compared to baseline (p < 0.001). Pain intensity scores decreased by ≥50% from baseline in all participants. Opioid analgesia was discontinued by 90% (n = 8) of participants. CONCLUSION: Whilst it is already recognised that SCS reduces pain in FBSS, this study demonstrated that it also reduced the symptoms of anxiety and depression with an associated reduction in opioid consumption.
Assuntos
Ansiedade/etiologia , Dor Crônica/etiologia , Depressão/etiologia , Síndrome Pós-Laminectomia/complicações , Síndrome Pós-Laminectomia/psicologia , Estimulação da Medula Espinal/métodos , Ansiedade/psicologia , Dor Crônica/psicologia , Depressão/psicologia , Síndrome Pós-Laminectomia/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do TratamentoRESUMO
BACKGROUND: Consensus is lacking regarding the optimal operation for transposition, ventricular septal defect, and pulmonary stenosis. METHODS: Between 1968 and 2012, a total of 76 patients underwent the Rastelli procedure, with 52 mid- or long-term survivors. A bracketing analysis was used to estimate the likelihood of late left ventricular outflow tract obstruction (LVOTO). RESULTS: Early mortality decreased over the period of study, with no hospital mortality since 2000. Among one year survivors, 10- and 20-year survival was 90% and 72%, respectively. Freedom from reoperation for LVOTO was 87% at 20 years, with no increase in risk among patients having the procedure before 5 years of age. Available late echocardiographic or catheterization data indicated mild or no LVOTO at a median of 14.3 years in a subset of 38 patients. Estimated freedom from major LVOTO at 20 years is bracketed between the estimate of 87% freedom from reoperation for LVOTO at 20 years and the 78% freedom from reoperation for LVOTO or cardiac death by 20 years. CONCLUSION: The Rastelli operation can be performed in the current era with an early mortality that approaches 0% and with 20-year survival that exceeds 70%. The late risk of important LVOTO appears to range from about 13% to 22% at 20 years, with no increase in risk among patients operated upon before the age of 5 years.
Assuntos
Transposição das Grandes Artérias/efeitos adversos , Previsões , Complicações Pós-Operatórias , Transposição dos Grandes Vasos/cirurgia , Obstrução do Fluxo Ventricular Externo/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Mortalidade Hospitalar/tendências , Humanos , Lactente , Recém-Nascido , Masculino , Reoperação , Estudos Retrospectivos , Sobreviventes , Resultado do Tratamento , Obstrução do Fluxo Ventricular Externo/mortalidade , Obstrução do Fluxo Ventricular Externo/cirurgia , Adulto JovemAssuntos
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Técnicas de Diagnóstico Cardiovascular/normas , Intervenção Médica Precoce/normas , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/terapia , Rabdomioma/diagnóstico , Rabdomioma/terapia , Esclerose Tuberosa/complicações , Animais , Antineoplásicos/uso terapêutico , Arritmias Cardíacas/genética , Procedimentos Cirúrgicos Cardíacos/normas , Consenso , Ecocardiografia/normas , Eletrocardiografia/normas , Predisposição Genética para Doença , Testes Genéticos/normas , Neoplasias Cardíacas/genética , Humanos , Imageamento por Ressonância Magnética/normas , Fenótipo , Valor Preditivo dos Testes , Rabdomioma/genética , Resultado do Tratamento , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genéticaRESUMO
BACKGROUND: In 2010, the Tennessee Department of Health, in collaboration with the Centers for Disease Control and Prevention (CDC), expanded influenza surveillance in Tennessee to include other respiratory viruses. OBJECTIVES: To determine the prevalence and seasonality of influenza and other respiratory viruses during the influenza seasons of 2010-2012. METHODS: Nasal and nasopharangeal swabs/washings from persons with influenza-like illness were collected across Tennessee. Influenza and other respiratory viruses were identified using a molecular-based respiratory virus panel. Influenza A positives were subtyped using real-time PCR according to the CDC protocol. Data were analyzed to describe frequency and seasonality of circulating strains. RESULTS: Of the 933 positive specimens, 60·3% were identified as influenza viruses, 19·8% rhinovirus/enterovirus, 8·6% respiratory syncytial virus (RSV), 5·8% metapneumovirus, 3·0% adenovirus, and 2·5% parainfluenza viruses. In the 2010-2011 season, influenza B was prominent during weeks 48-3, while influenza A(H1N1) was most frequently identified during weeks 4-10. Influenza A(H3N2) was present at lower levels during weeks 48-17. However, in the 2011-2012 season, overall numbers of influenza cases were reduced and influenza A (H3N2) was the most abundant influenza strain. The expanded surveillance for other respiratory viruses noted an increase in identified specimens from the first to the second season for adenovirus, metapneumovirus, RSV, and rhinovirus/enterovirus. CONCLUSIONS: This study provides data of the influenza strains in circulation in Tennessee. It also establishes a baseline and time of year to expect other respiratory viruses that will aid in detecting outbreaks of non-influenza respiratory viruses in Tennessee.
Assuntos
Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/virologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Viroses/epidemiologia , Viroses/virologia , Vírus/isolamento & purificação , Monitoramento Epidemiológico , Humanos , Cavidade Nasal/virologia , Nasofaringe/virologia , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Estações do Ano , Tennessee/epidemiologia , Vírus/classificaçãoRESUMO
A novel technique of valve-sparing aortic root replacement was applied to 2 children younger than 3 years of age with Marfan syndrome and large aortic root aneurysms. Using elements of both the remodeling and reimplantation techniques, circumferential rings from a 20-mm to 22-mm polyester graft provide stabilization at the subannular and sinotubular levels, and bovine pericardial patches create pseudosinuses. Follow-up at 2 years in 1 patient and 7 months in a second patient revealed satisfactory valve function with stable aortic root size.
Assuntos
Aneurisma Aórtico/cirurgia , Valva Aórtica/cirurgia , Implante de Prótese Vascular/métodos , Síndrome de Marfan/cirurgia , Pré-Escolar , Humanos , LactenteRESUMO
In a cohort of patients with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), genetic testing is useful in confirming the diagnosis, particularly in individuals who do not completely fulfil Task Force criteria for the disease, thereby also enabling the adoption of preventive measures in family members. Due to the high percentage of novel mutations that are expected to be identified in ARVC/D, the use of genetic screening technology based on the identification of known mutations seems to have very restricted value. Our results support that the presence of certain genetic variations could play a role in the final phenotype of patients with ARVC/D, where single and compound mutation carriers would have more symptomatic forms of the disease and the polymorphism P366L could be associated to a more benign phenotype.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Testes Genéticos , Adulto , Displasia Arritmogênica Ventricular Direita/diagnóstico , Estudos de Coortes , Desmocolinas/genética , Desmogleína 2/genética , Desmoplaquinas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Placofilinas/genética , Polimorfismo GenéticoRESUMO
The response of forest insect communities to disturbances such as timber harvest will likely depend on the underlying spatial structure of species assemblages before the disturbance occurs. Unfortunately, many studies of forest management implicitly assume homogeneity of community structure before harvest; postlogging communities are inferred to be a direct product of the imposed management. The goal of this study is to examine variation in the community structure of forest Lepidoptera using the pretimber harvest data on Lepidoptera from 20 forest sites within three watersheds at Morgan Monroe State Forest, IN. A total of 14,537 individuals representing 324 species of Lepidoptera were sampled from Morgan-Monroe State Forest in 2007. Sampling efficiency was not a function of management unit, and, surprisingly, we found little evidence that management units differed in overall community composition. Diversity partitioning suggested that > 99% of Simpson diversity (species dominance) was determined at the local scale, and each site contained the same 10 dominant taxa in rank order. Variation in species richness seemed to be more a problem of sampling bias than underlying differences in habitat preference by moth feeding guilds. Finally, Mantel tests suggested that forest moth communities at Morgan-Monroe are not spatially autocorrelated. The results here are encouraging because they strongly suggest that shifts in lepidopteran community structure should reflect the community response to disturbance rather than inherent spatial heterogeneity of species composition.
Assuntos
Biodiversidade , Lepidópteros , Árvores , Animais , Carya , Indiana , QuercusRESUMO
OBJECTIVE: In 1990, Fontan, Kirklin, and colleagues published equations for survival after the so-called "Perfect Fontan" operation. After 1988, we evolved a protocol using an internal or external polytetraflouroethylene tube of 16 to 19 millimetres diameter placed from the inferior caval vein to either the right or left pulmonary artery along with a bidirectional cava-pulmonary connection. The objective of this study was to test the hypothesis that a "perfect" outcome is routinely achievable in the current era when using a standardized surgical procedure. METHODS: Between 1 January, 1988, and 12 December, 2005, 112 patients underwent the Fontan procedure using an internal or external polytetraflouroethylene tube plus a bidirectional cava-pulmonary connection, the latter usually having been constructed as a previous procedure. This constituted 45% of our overall experience in constructing the Fontan circulation between 1988 and 1996, and 96% of the experience between 1996 and 2005. Among all surviving patients, the median follow-up was 7.3 years. We calculated the expected survival for an optimal candidate, given from the initial equations, and compared this to our entire experience in constructing the Fontan circulation. RESULTS: An internal tube was utilized in 61 patients, 97% of whom were operated prior to 1998, and an external tube in 51 patients, the latter accounting for 95% of all operations since 1999. At 1, 5, 10 and 15 years, survival of the entire cohort receiving polytetraflouroethylene tubes is superimposable on the curve calculated for a "perfect" outcome. Freedom from replacement or revision of the tube was 97% at 10 years. CONCLUSION: Using a standardized operative procedure, combining a bidirectional cavopulmonary connection with a polytetraflouroethylene tube placed from the inferior caval vein to the pulmonary arteries for nearly all patients with functionally univentricular hearts, early and late survival within the "perfect" outcome as predicted by the initial equations of Fontan and Kirklin is routinely achievable in the current era. The need for late revision or replacement of the tube is rare.
Assuntos
Técnica de Fontan , Técnica de Fontan/instrumentação , Técnica de Fontan/métodos , Técnica de Fontan/mortalidade , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/cirurgia , Humanos , Análise Multivariada , Politetrafluoretileno , Reoperação , Resultado do TratamentoRESUMO
Aortopulmonary (AP) window is an extremely rare congenital anomaly involving a communication between the ascending aorta and pulmonary artery. Two-dimensional transthoracic echocardiography is traditionally used in the diagnosis but has limitations. We report the usefulness of three-dimensional transthoracic echocardiography in the assessment of AP window in two newborns studied by us.
Assuntos
Defeito do Septo Aortopulmonar/diagnóstico por imagem , Ecocardiografia Tridimensional , Defeito do Septo Aortopulmonar/cirurgia , Humanos , Recém-Nascido , MasculinoRESUMO
Colony-stimulating factors and other cytokines signal via their cognate receptors to regulate hematopoiesis. In many developmental systems, inductive signalling determines cell fate and, by analogy with this, it has been postulated that cytokines, signalling via their cognate receptors, may play an instructive role in lineage specification in hematopoiesis. An alternative to this instructive hypothesis is the stochastic or permissive hypothesis. The latter proposes that commitment to a particular hematopoietic lineage is an event that occurs independently of extrinsic signals. It predicts that the role of cytokines is to provide nonspecific survival and proliferation signals. In this review, we look at the role of cytokine receptor signalling in hematopoiesis and consider the evidence for both hypotheses. Data from experiments that genetically manipulate receptor gene expression in vitro or in vivo are reviewed. Experiments in which cytokine receptors were installed in multipotential cells showed that, in some cases, stimulation with the cognate ligand could lead to alterations in lineage output. The creation of genetically manipulated mouse strains demonstrated that cytokine receptors are required for expansion and survival of single lineages but did not reveal a role in lineage commitment. We conclude that hematopoietic differentiation involves mainly stochastic events, but that cytokine receptors also have some instructive role.
Assuntos
Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Receptores de Citocinas/fisiologia , Animais , Linhagem da Célula/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Receptores de Citocinas/classificaçãoRESUMO
H. pylori infection accounts for most cases of gastric cancer, but the initiating events remain unclear. The principal H. pylori pathogenicity-associated CagA protein disrupts intracellular SHP-2 signalling pathways including those used by the IL-6 family cytokines, IL-6 and IL-11. Imbalanced IL-6 family cytokine signalling in the gp130(757FF) mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP-2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia. In a cohort of patient gastric biopsies with known H. pylori and CagA status, we investigated whether (i) STAT3 and ERK1/2 activation is altered in H. pylori-dependent gastritis; (ii) these profiles are more pronounced in CagA+ H. pylori infection; and (iii) the expression of pro-inflammatory cytokines that activate STAT3 and ERK 1/2 pathways is associated with progression to gastric cancer. IL-6, IL-11, and activated STAT3 and ERK1/2 were quantified in antral biopsies from gastritic stomach, metaplastic tissue, and resected gastric cancer tissues. We observed significantly increased STAT3 and ERK1/2 activation (p = 0.001) in H. pylori-dependent gastritis, which was further enhanced in the presence of CagA+ H. pylori strains. Of known gastric ligands that drive STAT3 activation, IL-6 expression was increased after H. pylori infection and both IL-6 and IL-11 were strongly up-regulated in the gastric cancer biopsies. This suggests a mechanism by which IL-11 drives STAT3 activation and proliferation during gastric cancer progression. We addressed this using an in vitro approach, demonstrating that recombinant human IL-11 activates STAT3 and concomitantly increases proliferation of MKN28 gastric epithelial cells. In summary, we show increased STAT3 and ERK1/2 activation in H. pylori-dependent gastritis that is likely driven in an IL-6-dependent fashion. IL-11 expression is associated with adenocarcinoma development, but not gastritic lesions, and we identify a novel mechanism for IL-11 as a potent inducer of proliferation in the human gastric cancer setting.
Assuntos
Interleucina-6/metabolismo , Neoplasias Gástricas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Biópsia , Proliferação de Células , Progressão da Doença , Ativação Enzimática , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/metabolismo , Gastrite/microbiologia , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/complicações , Helicobacter pylori , Humanos , Interleucina-11/metabolismo , Interleucina-8/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas de Neoplasias/metabolismo , Inibidores da Bomba de Prótons , Antro Pilórico/microbiologia , Antro Pilórico/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
The enteric nervous system arises from vagal (caudal hindbrain) and sacral level neural crest-derived cells that migrate into and along the developing gut. Data from previous studies have suggested that (i) there may be gradients along the gut that induce the caudally directed migration of vagal enteric neural precursors (ENPs), (ii) exposure to the caecum might alter the migratory ability of vagal ENPs and (iii) Sema3A might regulate the entry into the hindgut of ENPs derived from sacral neural crest. Using co-cultures we show that there is no detectable gradient of chemoattractive molecules along the pre-caecal gut that specifically promotes the caudally directed migration of vagal ENPs, although vagal ENPs migrate faster caudally than rostrally along explants of hindgut. Exposure to the caecum did not alter the rate at which ENPs colonized explants of hindgut, but it did alter the ability of ENPs to colonize the midgut. The co-cultures also revealed that there is localized expression of a repulsive cue in the distal hindgut, which might delay the entry of sacral ENPs. We show that Sema3A is expressed by the hindgut mesenchyme and its receptor, neuropilin-1, is expressed by migrating ENPs. Furthermore, there is premature entry of sacral ENPs and extrinsic axons into the distal hindgut of fetal mice lacking Sema3A. These data show that Sema3A expressed by the distal hindgut regulates the entry of sacral ENPs and extrinsic axons into the hindgut. ENPs did not express neuropilin-2 and there was no detectable change in the timetable by which ENPs colonize the gut in mice lacking neuropilin-2.
Assuntos
Movimento Celular/fisiologia , Sistema Digestório/inervação , Sistema Digestório/metabolismo , Sistema Nervoso Entérico/citologia , Sistema Nervoso Entérico/embriologia , Crista Neural/citologia , Semaforina-3A/metabolismo , Animais , Sistema Digestório/embriologia , Imuno-Histoquímica , Hibridização In Situ , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Neuropilina-1/metabolismoRESUMO
Microtubules function as molecular tracks along which motor proteins transport a variety of cargo to discrete destinations within the cell. The carboxyl termini of alpha- and beta-tubulin can undergo different posttranslational modifications, including polyglutamylation, which is particularly abundant within the mammalian nervous system. Thus, this modification could serve as a molecular "traffic sign" for motor proteins in neuronal cells. To investigate whether polyglutamylated alpha-tubulin could perform this function, we analyzed ROSA22 mice that lack functional PGs1, a subunit of alpha-tubulin-selective polyglutamylase. In wild-type mice, polyglutamylated alpha-tubulin is abundant in both axonal and dendritic neurites. ROSA22 mutants display a striking loss of polyglutamylated alpha-tubulin within neurons, including their neurites, which is associated with decreased binding affinity of certain structural microtubule-associated proteins and motor proteins, including kinesins, to microtubules purified from ROSA22-mutant brain. Of the kinesins examined, KIF1A, a subfamily of kinesin-3, was less abundant in neurites from ROSA22 mutants in vitro and in vivo, whereas the distribution of KIF3A (kinesin-2) and KIF5 (kinesin-1) appeared unaltered. The density of synaptic vesicles, a cargo of KIF1A, was decreased in synaptic terminals in the CA1 region of hippocampus in ROSA22 mutants. Consistent with this finding, ROSA22 mutants displayed more rapid depletion of synaptic vesicles than wild-type littermates after high-frequency stimulation. These data provide evidence for a role of polyglutamylation of alpha-tubulin in vivo, as a molecular traffic sign for targeting of KIF1 kinesin required for continuous synaptic transmission.