RESUMEN
Ankle osteoarthritis (OA) is a debilitating condition that arises as a result of trauma or injury to the ankle and often progresses to chronic pain and loss of function that may require surgical intervention. Total ankle arthroplasty (TAA) has emerged as a means of operative treatment for end-stage ankle OA. Increased hospital length of stay (LOS) is a common adverse postoperative outcome that increases both the complications and cost of care associated with arthroplasty procedures. The purpose of this study was to employ four machine learning (ML) algorithms to predict LOS in patients undergoing TAA using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. The ACS-NSQIP database was queried to identify adult patients undergoing elective TAA from 2008 to 2018. Four supervised ML classification algorithms were utilized and tasked with predicting increased hospital length of stay (LOS). Among these variables, female sex, ASA Class III, preoperative sodium, preoperative hematocrit, diabetes, preoperative creatinine, other arthritis, BMI, preoperative WBC, and Hispanic ethnicity carried the highest importance across predictions generated by 4 independent ML algorithms. Predictions generated by these algorithms were made with an average AUC of 0.7257, as well as an average accuracy of 73.98% and an average sensitivity and specificity of 48.47% and 79.38%, respectively. These findings may be useful for guiding decision-making within the perioperative period and may serve to identify patients at increased risk for a prolonged LOS.
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Osteosarcoma (OS) is a primary bone malignancy characterized by an aggressive nature, limited treatment options, low survival rate, and poor patient prognosis. Conditionally replicative adenoviruses (CRAds) armed with immune checkpoint inhibitors hold great potential for enhanced therapeutic efficacy. The present study aims to investigate the anti-tumor efficacy of CAV2-AU-M2, a CAV2-based CRAd armed with an anti-PD-1 single-domain antibody (sdAb), against OS cell lines in vitro. The infection, conditional replication, cytopathic effects, and cytotoxicity of CAV2-AU-M2 were tested in four different OS cell lines in two-dimensional (2D) and three-dimensional (3D) cell cultures. CAV2-AU-M2 showed selective replication in the OS cells and induced efficient tumor cell lysis and death. Moreover, CAV2-AU-M2 produced an anti-PD-1 sdAb that demonstrated effective binding to the PD-1 receptors. This study demonstrated the first CRAd armed with an anti-PD-1 sdAb. This combined approach of two distinct immunotherapies is intended to enhance the anti-tumor immune response in the tumor microenvironment.
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Neoplasias Óseas , Viroterapia Oncolítica , Virus Oncolíticos , Osteosarcoma , Anticuerpos de Dominio Único , Humanos , Viroterapia Oncolítica/métodos , Osteosarcoma/terapia , Neoplasias Óseas/terapia , Microambiente TumoralRESUMEN
MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and canine diseases. Most cancers tested to date have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process. Based on this evidence, numerous miRNAs have been suggested as potential cancer biomarkers for both diagnosis and prognosis. miRNA-based therapies have also been tested in different cancers and have provided measurable clinical benefits to patients. In addition, understanding miRNA biogenesis and regulatory mechanisms in cancer can provide important knowledge about resistance to chemotherapies, leading to more personalized cancer treatment. In this review, we comprehensively summarized the importance of miRNA in human and canine cancer research. We discussed the current state of development and potential for the miRNA as both a diagnostic marker and a therapeutic target.
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MicroARNs , Neoplasias , Humanos , Animales , Perros , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
Genetically modified oncolytic adenoviruses have been proposed as a vehicle for cancer therapy. However, several concerns, such as toxicity to normal cells and organs, lack of suitable cell surface receptors to allow viral entry to the desired cell type(s), and activation of both innate and adaptive immune systems in patients, restrict the successful clinical application of adenoviral-mediated cancer gene therapy. Successful virotherapy will require efficient transductional and transcriptional targeting to enhance therapeutic efficacy by ensuring targeted adenoviral infection, replication, and/or therapeutic transgene expression. Targeted modification of viral components, such as viral capsid, fiber knob, and the insertion of transgenes for expression, are prerequisites for the necessary transductional and transcriptional targeting of adenovirus. However, the conventional approach to modify the adenoviral genome is complex, time consuming, and expensive. It is dependent on the presence of unique restriction enzyme sites that may or may not be present in the target location. Clustered regularly interspaced short palindromic repeat (CRISPR) along with the RNA-guided nuclease Cas9 (CRISPR/Cas9) is one of the most powerful tools that has been adopted for precise genome editing in a variety of cells and organisms. However, the ability of the CRISPR/Cas9 system to precisely and efficiently make genetic modification, as well as introduce gene replacements, in adenoviral genomes, remains essentially unknown. Herein the ability of in vitro CRISPR/CAS9-mediated editing of the canine adenovirus type 2 (CAV2) genome to promote targeted modification of the viral genome was assessed. To demonstrate the feasibility of this goal, CRISPR/Cas9 has been used to successfully insert the RFP (red fluorescent protein) reporter construct into the CAV2 genome. Initial results demonstrated high efficiency and accuracy for in vitro CRISPR-mediated editing of the large CAV2 genome. Furthermore, this application was expanded, using multiple guide RNAs, to conduct gene replacement in the CAV2 genome by substituting a portion of the E3 gene with a construct designed to express a single chain antibody to canine PD-1. Thus, this work provides a significantly improved and efficient method for targeted editing of adenoviruses to generate altered and potentially therapeutic viral genomes in the shortest possible time.
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Adenovirus Caninos/genética , Edición Génica , Animales , Proteína 9 Asociada a CRISPR , Sistemas CRISPR-Cas , Línea Celular Tumoral , Perros , Genoma Viral , Viroterapia Oncolítica , Reparación del ADN por RecombinaciónRESUMEN
Class I PI3K enzymes are critical for the maintenance of effective immunity. In T cells, PI3Kα and PI3Kδ are activated by the TCR and costimulatory receptors, whereas PI3Kγ is activated by G protein-coupled chemokine receptors. PI3Kδ is a key regulator of regulatory T (Treg) cell function. PI3K isoform-selective inhibitors are in development for the treatment of diseases associated with immune dysregulation, including chronic inflammatory conditions, cancer, and autoimmune diseases. Idelalisib (PI3Kδ), alpelisib (PI3Kα), duvelisib (PI3Kδ/γ), and copanlisib (pan-PI3K) have recently been approved for use in cancer treatment. Although effective, these therapies often have severe side effects associated with immune dysregulation and, in particular, loss of Treg cells. Therefore, it is important to gain a better understanding of the relative contribution of different PI3K isoforms under homeostatic and inflammatory conditions. Experimental autoimmune encephalitis is a mouse model of T cell-driven CNS inflammation, in which Treg cells play a key protective role. In this study, we show that PI3Kδ is required to maintain normal Treg cell development and phenotype under homeostatic conditions but that loss of PI3Kδ alone in Treg cells does not lead to autoimmunity. However, combined loss of PI3Kα and PI3Kδ signaling resulted in increased experimental autoimmune encephalitis disease severity. Moreover, mice lacking PI3Kα and PI3Kδ in Treg cells developed spontaneous peripheral nerve inflammation. These results show a key role for PI3K signaling in Treg cell-mediated protection against CNS inflammation.
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Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Nervios Periféricos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/diagnóstico , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Nervios Periféricos/patología , Índice de Severidad de la Enfermedad , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
BACKGROUND: The Grand Rapids Arch Collapse Classification system was devised in 2011 to assist physicians' and patients' understanding of the mechanisms underlying arch collapse. Five types of arch collapse are described, based on which part of the foot or ankle is affected. The purpose of this study was to determine the inter- and intrarater reliability of this classification system when used by physicians with various levels of training. METHODS: A senior author identified a stratified selection of 50 patients (10 per classification type) who presented with foot/ankle pain and suitable radiographs. A survey was designed using prediagnosis radiographs and clinical synopses of the patient's chart. The survey consisted of a description of the classification scheme and the 50 cases in a randomized order. Eight weeks later, they repeated the test to analyze for intra-rater agreement. RESULTS: Of the 33 physicians who received the survey, 26 completed the first round (16 attendings, 4 foot and ankle fellows, and 6 residents). Overall, there was substantial agreement among raters in all five types. Kappa scores for each type were 0.72, 0.65, 0.72, 0.70, 0.63, respectively. The combined kappa score was 0.68. After 8 weeks, 13 of the 26 participants repeated the study. A Kappa analysis was once again performed for the 13 respondents, which produced a substantial level of agreement with a value of 0.74 for intrarater reliability. CONCLUSION: The Grand Rapids Arch Collapse Classification system was designed to provide an accessible mechanism for physicians to consistently describe arch collapse, its effects, and the conditions associated with it. The utility of this system is wholly reliant on the repeatability among clinicians. This study has demonstrated that the classification system has substantial rates of reliability among physicians of different levels of experience and training. LEVEL OF EVIDENCE: Level IV.
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PURPOSE: Circumferential speckle tracking carotid artery strain is a novel method of quantifying vessel wall stiffness. We hypothesized that carotid wall stiffness would be associated with carotid intimal medial thickening (a medial process associated with risk factors), but not coronary artery disease (an intimal process). METHODS: Bilateral carotid artery ultrasound was conducted on outpatients who had previously undergone elective coronary angiography. Mean carotid artery far wall circumferential strain (FWCS) was assessed for correlations with coronary angiographic stenosis, cardiac risk factors, carotid intima-media thickness (CIMT), and carotid plaque. RESULTS: One hundred and sixty five (165) patients were studied. No significant association was found between the presence of coronary artery disease on angiography and mean FWCS. FWCS was higher in current tobacco smokers. In addition, carotid strain was found to decrease with increased age (r = -0.33, P < 0.001). When adjusted for pulse pressure (PP), FWCS/PP was negatively correlated with mean CIMT (r = -0.29, P = 0.002) and bulb maximum plaque height (r = -0.27, P = 0.004). Hypertension and diabetes were associated with decreased FWCS/PP (increased wall stiffness). CONCLUSIONS: While no clear relationship between carotid strain and coronary artery disease was observed, increased CIMT, carotid plaque, and cardiac risk factors were associated with decreased carotid strain. Further work is required to explore the relationship between carotid strain and cardiovascular events.
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Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Grosor Intima-Media Carotídeo/estadística & datos numéricos , Placa Aterosclerótica/diagnóstico por imagen , Ultrasonografía/métodos , Rigidez Vascular , Anciano , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/fisiopatologíaRESUMEN
BACKGROUND: Right ventricular systolic pressure (RVSP) estimated by echocardiography is critical for the initial screening and follow-up of pulmonary hypertension (PH). Inter-observer variability (IOV) in RVSP can impact clinical decision making. This study assessed whether a simple guideline-based teaching intervention could reduce the IOV in RVSP interpretation. METHODS AND RESULTS: Eleven participants in a high-volume tertiary level echocardiography laboratory underwent an assessment of the baseline IOV in the assessment of RVSP for a series of transthoracic echocardiograms (TTE), depicting various degrees of PH among 8 cases each before and after a teaching intervention. The inter-observer variance (root-mean-square error) decreased from 26.0 mm Hg2 (5.1 mm Hg) at baseline to 5.8 mm Hg2 (2.4 mm Hg) post-teaching intervention (P = .025). The corresponding inter-class coefficient (ICC) increased from 0.89 to 0.98. Several factors relating to image acquisition and interpretation were identified as contributing to IOV in RVSP. The outcome was the development of a practical tool to mitigate these factors. CONCLUSIONS: A simple structured teaching intervention successfully reduced IOV in the measurement of RVSP in a high-volume echo laboratory.
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Ecocardiografía/métodos , Ecocardiografía/normas , Hipertensión Pulmonar/diagnóstico por imagen , Variaciones Dependientes del Observador , Control de Calidad , Humanos , Hipertensión Pulmonar/fisiopatologíaRESUMEN
Interleukin-7 (IL-7) is essential for the development of T cells in humans and mice where deficiencies in IL-7 signaling result in severe immunodeficiency. T cells require IL-7 at multiple points during development; however, it is unclear when IL-7 is first necessary. We observed that mice with impaired IL-7 signaling had a large reduction in the number of early thymic progenitors (ETPs) while mice that overexpress IL-7 had greatly increased numbers of ETPs. These results indicated that the development of ETPs is sensitive to IL-7. Bone marrow progenitors of ETP are present in normal numbers in mice with impaired IL-7 signaling (IL-7Rα449F) and were efficiently recruited to the thymus. Furthermore, ETPs and their progenitors from IL-7Rα449F mice did not undergo increased apoptosis and proliferate normally compared to WT cells. Mixed bone marrow chimeras demonstrated that IL-7 signaling has a cell-intrinsic role in ETP development but was not required for development of bone marrow progenitors. We have shown a novel role for IL-7 signaling in the development of ETPs that is distinct from classic mechanisms of IL-7 regulating survival and proliferation.
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Células de la Médula Ósea/fisiología , Interleucina-7/metabolismo , Linfocitos T/fisiología , Timo/inmunología , Animales , Diferenciación Celular , Linaje de la Célula , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Humanos , Linfopoyesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-7/genética , Transducción de SeñalRESUMEN
A 28-year-old woman was referred to our institution with sudden onset chest pain at rest. Electrocardiography revealed an inferoposterior ST-segment elevation myocardial infraction. The patient proceeded to cardiac catheterization, which revealed a large ectatic left circumflex coronary artery with an apparent fistula connecting it to the coronary sinus. Follow-up angiography revealed that the fistula was no longer patent, spontaneously thrombosed, and resolved without requiring surgery.
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Anomalías de los Vasos Coronarios/complicaciones , Fístula/complicaciones , Trombosis/etiología , Adulto , Cateterismo Cardíaco , Angiografía Coronaria , Seno Coronario , Anomalías de los Vasos Coronarios/diagnóstico , Electrocardiografía , Femenino , Fístula/diagnóstico , Humanos , Trombosis/diagnósticoRESUMEN
BACKGROUND: Infections in total ankle arthroplasty are a serious complication, about which there is little information in the current literature. METHODS: This is a retrospective review of infected total ankle arthroplasty at one institution from 1995 to 2012. Risk factors were compared between patients with infected total ankle arthroplasty and age- and sex-matched patients who did not have infection (control patients) within the same time period. RESULTS: 966 patients with total ankle arthroplasty were reviewed, and 29 cases of infected total ankle arthroplasty (3.2%) were identified. The incidence of infection in primary ankle arthroplasty was 2.4% and in revision arthroplasty was 4%. Risk factors for infection in our cohort included diabetes, prior ankle surgery, and wound healing problems more than 14 days postoperatively. No significant difference was found between groups with respect to risk factors including smoking, body mass index, and operative time. At latest follow-up, none of the patients had signs of persistent infection. Operative intervention of infected total ankle arthroplasty resulted in limb salvage in 79% of cases (a 21% amputation rate). At final follow-up, 65.5% of cases were infection-free with retained arthroplasty. This was achieved by irrigation and debridement alone, 1-stage fusion, and most often 2-stage revision. The final outcome was fusion in 3 of 29 cases (10.3%). CONCLUSIONS: Given the morbidity of infected ankle arthroplasty, careful consideration should be made about performing arthroplasty in patients with multiple prior surgeries and comorbidities that predispose to wound-healing difficulties. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
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Artroplastia de Reemplazo de Tobillo/efectos adversos , Prótesis Articulares/efectos adversos , Infecciones Relacionadas con Prótesis/etiología , Infecciones Relacionadas con Prótesis/terapia , Adulto , Anciano , Amputación Quirúrgica/estadística & datos numéricos , Antibacterianos/uso terapéutico , Estudios de Casos y Controles , Desbridamiento , Complicaciones de la Diabetes , Femenino , Humanos , Recuperación del Miembro , Masculino , Persona de Mediana Edad , Reoperación , Estudios Retrospectivos , Factores de Riesgo , Dehiscencia de la Herida Operatoria/etiología , Irrigación TerapéuticaAsunto(s)
Traumatismos del Tobillo/clasificación , Fracturas Óseas/clasificación , Astrágalo/lesiones , Terminología como Asunto , Traumatismos del Tobillo/diagnóstico , Traumatismos del Tobillo/terapia , Fracturas Óseas/diagnóstico , Fracturas Óseas/terapia , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los ResultadosRESUMEN
IL-7 is critical for murine T and B cell development and survival and plays a significant role in lymphoblastic leukemia in both humans and mice. We evaluated the role of the IL-7Rα Tyr(449) cytoplasmic SH2-binding motif in IL-7-mediated B cell development using a knock-in mouse with a Tyr to Phe mutation (IL-7Rα(449F/449F) mouse). IL-7Rα(449F/449F) and IL-7Rα(-/-) mice showed no defect in the number of pre-pro-B cells, although IL-7Rα(449F/449F) mice had decreased Ebf1 in pre-pro-B cells and impairment in B cell-committed CLPs. We identified that IL-7Rα Tyr(449) was critical for both pro-B and pre-B stages of development in the bone marrow. IL-7Rα(449F/449F) and IL-7Rα(-/-) mice had comparable precursor B cell defects, indicating that signaling from the IL-7Rα required this motif. Although the defect in IL-7Rα(449F/449F) pro-B cells was associated with loss of STAT5 activation and diminished expression of Mcl1, this was not rescued by overexpression of Bcl-2. IL-7Rα(449F/449F) and IL-7Rα(-/-) pre-B cells also showed defective cyto-Igµ and CD25 expression, associated with reduced levels of Rag1, Rag2, and Irf4. Pre-B cells from IL-7Rα(449F/449F) mice also failed to proliferate, perhaps as a result of the failure to rearrange Igµ. Our data suggest that IL-7Rα Tyr(449) was essential for IL-7Rα signaling in bone marrow B cell development and survival.
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Médula Ósea/inmunología , Diferenciación Celular/inmunología , Mutación Missense , Células Precursoras de Linfocitos B/inmunología , Receptores de Interleucina-7/inmunología , Transducción de Señal/inmunología , Sustitución de Aminoácidos , Animales , Diferenciación Celular/genética , Proliferación Celular , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Reordenamiento Génico de Linfocito B/genética , Reordenamiento Génico de Linfocito B/inmunología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Humanos , Cadenas mu de Inmunoglobulina/genética , Cadenas mu de Inmunoglobulina/inmunología , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Ratones , Ratones Noqueados , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/inmunología , Células Precursoras de Linfocitos B/citología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Receptores de Interleucina-7/genética , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/inmunología , Transducción de Señal/genética , Tirosina/genética , Tirosina/inmunologíaRESUMEN
IL-7 is a critical cytokine for lymphocyte development. Recent work has highlighted critical roles for IL-7 signaling in mature T cell homeostasis and function, but its role in B cells is less well characterized. Using a knock-in mouse possessing a Tyr to Phe mutation at position 449 (IL-7Rα(449F/449F) mice) within the cytoplasmic SH2-binding motif of IL-7Rα, we evaluated the role of IL-7Rα Y449 motif in spleen B cells. IL-7Rα(449F/449F) mice had reduced numbers and increased death of follicular B cells compared to WT, but had significantly more follicular cells than IL-7Rα(-/-). The death of IL-7Rα(449F/449F) follicular cells was not due to a failure to respond to BAFF or lower levels of BAFF, a critical B cell survival factor. Marginal zone B cells were unaffected by the IL-7Rα(449F/449F) mutation. Any role for TSLP was ruled out, as TSLPR(-/-) mice had an identical B cell phenotype to wild-type mice. Bone marrow chimeras and the absence of IL-7Rα on B cells suggested that IL-7 did not directly regulate mature B cells, but that an IL-7-responsive cell was influencing B cells. IL-7 was also critical at the checkpoint between the T1 and T2 stages in the spleen. IL-7Rα(-/-) mice fail to develop T2 cells, but IL-7Rα(449F/449F) show a reduction compared to WT but not complete absence of T2 cells. We also tested the functional responses of IL-7Rα(449F/449F) to antigens and infection and found no difference in antibody responses to T-dependent or T-independent antigens, or to Influenza/A. IL-7 was important for generation of antibody responses to the intestinal worm H. polygyrus and for naive levels of IgA. Taken together, this suggests that IL-7 regulates follicular B cell numbers and survival in a cell-extrinsic manner, via a bone-marrow derived cell, but is not critical for antibody production outside the gut.
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Linfocitos B/inmunología , Interleucina-7/inmunología , Receptores de Interleucina-7/inmunología , Transducción de Señal/inmunología , Sustitución de Aminoácidos , Animales , Anticuerpos Antivirales/sangre , Antígenos Virales/sangre , Factor Activador de Células B/genética , Factor Activador de Células B/inmunología , Linfocitos B/citología , Supervivencia Celular , Citocinas/genética , Citocinas/inmunología , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen , Inmunoglobulina G/sangre , Virus de la Influenza A/inmunología , Interleucina-7/genética , Ratones , Ratones Transgénicos , Dominios y Motivos de Interacción de Proteínas , Receptores de Interleucina-7/deficiencia , Receptores de Interleucina-7/genética , Bazo/citología , Bazo/inmunología , Linfopoyetina del Estroma TímicoRESUMEN
BACKGROUND: We hypothesized that internal fixation procedures performed on trauma intensive care unit (ICU) patients with systemic infections, some also febrile, would be at increased risk for deep infection. METHODS: A total of 128 patients (mean age, 37.4 years; mean Injury Severity Score [ISS], 34.7) admitted to the ICU with 179 femur or tibia fractures developed systemic infections. Systemic infections included sepsis, pneumonia, urinary tract infections, abdominal infections, and wound infections remote to the fracture. Of the fractures, 33 open and 146 closed underwent 150 intramedullary and 29 plate fixation procedures. Data were gathered regarding antibiotic use, systemic infection timing in relation to the date of fixation, and whether fever (>38.2°C) was present within 24 hours of fixation. Patients were followed up for a mean of 491 days. RESULTS: Twenty-eight procedures were performed a mean of 4.7 days after the diagnosis of a systemic infection, and 151 were performed a mean of 9.3 days before the diagnosis. Forty-five procedures were performed in patients who were febrile within 24 hours. Of the 179 procedures, 10 (5.6%) developed a deep infection. Four patients' implant infection was potentially hematogenously seeded with the same organism as their systemic infection. Neither the timing of the systemic infection in relation to the fixation procedure nor the presence of fever within 24 hours of fixation, days of preoperative antibiotics, location of the fracture, type of fixation (intramedullary nail vs. plate fixation), or type of systemic infection was significantly associated with the development of an infection. The only significant risk factor for developing an orthopedic infection was an open fracture (p < 0.001). CONCLUSION: Internal fixation performed in ICU patients with fever or in close conjunction to the diagnosis of systemic infection led to a 5.6% infection rate, which compares favorably with historic infection rates for fixation of open or closed tibia and femur fractures. LEVEL OF EVIDENCE: Therapeutic, level IV.
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Fracturas del Fémur/cirugía , Fiebre/complicaciones , Fijación Interna de Fracturas/efectos adversos , Infecciones/complicaciones , Infección de la Herida Quirúrgica/etiología , Fracturas de la Tibia/cirugía , Adulto , Femenino , Fracturas del Fémur/complicaciones , Fijación Intramedular de Fracturas/efectos adversos , Fracturas Cerradas/complicaciones , Fracturas Cerradas/cirugía , Fracturas Abiertas/complicaciones , Fracturas Abiertas/cirugía , Humanos , Puntaje de Gravedad del Traumatismo , Masculino , Estudios Retrospectivos , Factores de Riesgo , Fracturas de la Tibia/complicacionesRESUMEN
The immune response to viral infection is ideally rapid and specific, resulting in viral clearance and establishment of immune memory. Some viruses such as HIV can evade such responses leading to chronic infection, while others like Influenza A can elicit a severe inflammatory response with immune-related complications including death. Cytokines play a major role in shaping the appropriate outcomes to infection. While Interleukin-7 (IL-7) has a critical role in T and B cell development, treatment with IL-7 has recently been shown to aid the adaptive T cell response in clearance of chronic viral infection. In contrast, the IL-7-related cytokine thymic stromal lymphopoietin (TSLP) has a limited role in lymphocyte development but is important in the immune response to parasitic worms and allergens. The role for these cytokines in the immune response to an acute viral infection is unclear. IL-7 and TSLP share IL-7Rα as part of their heterodimeric receptors with the gamma common chain (γc) and TSLPR, respectively. We investigated the role of IL-7 and TSLP in the primary immune response to influenza A infection using hypomorphic IL-7Rα (IL-7Rα(449F)) and TSLPR(-/-) mice. We found that IL-7, but not TSLP, plays an important role in control of influenza A virus. We also showed that IL-7 signaling was necessary for the generation of a robust influenza A-specific CD4 and CD8 T cell response and that this requirement is intrinsic to CD8 T cells. These findings demonstrate a significant role for IL-7 during acute viral infection.
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Citocinas/metabolismo , Virus de la Influenza A/inmunología , Interleucina-7/metabolismo , Infecciones por Orthomyxoviridae/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Expresión Génica , Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , Ratones , Ratones Transgénicos , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/prevención & control , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores de Interleucina-7/metabolismo , Transducción de Señal , Linfopoyetina del Estroma TímicoRESUMEN
Regulatory T cells (Tregs) prevent autoimmunity and inflammation by suppressing the activation of other T cells and antigen presenting cells. The role of phosphoinositide 3-kinase (PI3K) signaling in Treg is controversial. Some studies suggest that inhibition of the PI3K pathway is essential for the development of Tregs whereas other studies have shown reduced Treg numbers and function when PI3K activity is suppressed. Here we attempt to reconcile the different studies that have explored PI3K and the downstream effectors Akt, Foxo, and mTOR in regulatory T cell development and function and discuss the implications for health and therapeutic intervention.
RESUMEN
PTEN, one of the most commonly mutated or lost tumor suppressors in human cancers, antagonizes signaling by the PI3K pathway. Mice with thymocyte-specific deletion of Pten rapidly develop peripheral lymphomas and autoimmunity, which may be caused by failed negative selection of thymocytes or from dysregulation of postthymic T cells. We induced conditional deletion of Pten from CD4 Th cells using a Cre knocked into the Tnfrsf4 (OX40) locus to generate OX40(Cre)Pten(f) mice. Pten-deficient Th cells proliferated more and produced greater concentrations of cytokines. The OX40(Cre)Pten(f) mice had a general increase in the number of lymphocytes in the lymph nodes, but not in the spleen. When transferred into wild-type (WT) mice, Pten-deficient Th cells enhanced anti-Listeria responses and the clearance of tumors under conditions in which WT T cells had no effect. Moreover, inflammatory responses were exaggerated and resolved later in OX40(Cre)Pten(f) mice than in WT mice. However, in contrast with models of thymocyte-specific Pten deletion, lymphomas and autoimmunity were not observed, even in older OX40(Cre)Pten(f) mice. Hence loss of Pten enhances Th cell function without obvious deleterious effects.
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Linfocitos T CD4-Positivos/inmunología , Homeostasis/inmunología , Fosfohidrolasa PTEN/inmunología , Animales , Autoinmunidad , Western Blotting , Citometría de Flujo , Técnicas de Sustitución del Gen , Activación de Linfocitos/inmunología , Linfoma/inmunología , Ratones , Ratones Transgénicos , Transducción de Señal/inmunologíaRESUMEN
The PI3K pathway has emerged as a key regulator of regulatory T cell (Treg) development and homeostasis and is required for full Treg-mediated suppression. To identify new genes involved in PI3K-dependent suppression, we compared the transcriptome of WT and p110δ(D910A) Tregs. Among the genes that were differentially expressed was the gene for the transmembrane cyclic ADP ribose hydrolase CD38. Here we show that CD38 is expressed mainly by a subset of Foxp3(+)CD25(+)CD4(+) T cells originating in the thymus and on Tregs in the spleen. CD38(high) WT Tregs showed superior suppressive activity to CD38(low) Tregs, which failed to upregulate CD73, a surface protein which is important for suppression. However, Tregs from heterozygous CD38(+/-) mice were unimpaired despite lower levels of CD38 expression. Therefore, CD38 can be used as a marker for Tregs with high suppressive activity and the impaired Treg function in p110δ(D910A) mice can in part be explained by the failure of CD38(high) cells to develop.
Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Linfocitos T Reguladores/enzimología , ADP-Ribosil Ciclasa 1/genética , Adenina/análogos & derivados , Adenina/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Genoma/genética , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/metabolismo , Ratones , Quinazolinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Tretinoina/farmacologíaRESUMEN
Lymphopenia-induced proliferation (LIP) is a proliferative program initiated in response to T cell insufficiency caused by acute or chronic immunodepletion. Studies of lymphopenic mice have demonstrated that the cytokine IL-7 and TCR signaling are critical for LIP. We examined how these two factors impact T cell proliferation following transfer into moderately lymphopenic mice. In this study, we show that moderate lymphopenia (â¼25% of wild-type lymphocytes) of IL-7Rα knock-in mutant (IL-7Rα(449F)) mice supports T cell proliferation, although with decreased frequency and kinetics compared with cells transferred to severely lymphopenic (5% of wild-type lymphocytes) IL-7Rα(-/-) hosts. Although previous studies have demonstrated that elevated IL-7 levels play an important role in LIP, IL-7 availability was not elevated in IL-7Rα(449F) mice. However, moderate lymphopenia increased access of transferred T cells to self-peptide presented on APCs that can trigger TCR signaling and proliferation. Importantly, we did not detect significant changes in TCR Vß usage of proliferated T cells recovered from either moderately or severely lymphopenic hosts. Our work demonstrates that polyclonal T cells retain a diverse TCR repertoire following proliferation mediated by either self-peptide-MHC interaction alone or in combination with IL-7, and that T cell reconstitution is most efficient in the presence of increased IL-7 availability.