RESUMEN
BACKGROUND: Acute incisional hernia incarceration is associated with high morbidity and mortality yet there is little evidence to guide which patients will benefit most from prophylactic repair. We explored baseline computed tomography (CT) characteristics associated with incarceration. METHODS: A case-control study design was utilized to explore adults (≥18 years) diagnosed with an incisional hernia between 2010 and 2017 at a single institution with a 1-year minimum follow-up. Computed tomography imaging at the time of initial hernia diagnosis was examined. Following propensity score matching for baseline characteristics, multivariable logistic regression was performed to identify independent predictors associated with acute incarceration. RESULTS: A total of 532 patients (27.26% male, mean 61.55 years) were examined, of whom 238 experienced an acute incarceration. Between two well-matched cohorts with and without incarceration, the presence of small bowel in the hernia sac (odds ratio [OR], 7.50; 95% confidence interval [CI], 3.35-16.38), increasing sac height (OR, 1.34; 95% CI, 1.10-1.64), more acute hernia angle (OR, 0.98 per degree; 95% CI, 0.97-0.99), decreased fascial defect width (OR, 0.68; 95% CI, 0.58-0.81), and greater outer abdominal fat (OR, 1.28; 95% CI, 1.02-1.60) were associated with acute incarceration. Using threshold analysis, a hernia angle of <91 degrees and a sac height of >3.25 cm were associated with increased incarceration risk. CONCLUSION: Computed tomography features present at the time of hernia diagnosis provide insight into later acute incarceration risk. Improved understanding of acute incisional hernia incarceration can guide selection for prophylactic repair and thereby may mitigate the excess morbidity associated with incarceration. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.
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Hernia Ventral , Hernia Incisional , Adulto , Humanos , Masculino , Femenino , Hernia Incisional/diagnóstico por imagen , Hernia Incisional/cirugía , Estudios de Casos y Controles , Hernia , Tomografía Computarizada por Rayos X/métodos , Hernia Ventral/cirugía , HerniorrafiaRESUMEN
BACKGROUND: We sought to explore the impact of sex, race, and insurance status on operative management of incisional hernias. METHODS: A retrospective cohort study was conducted to explore adult patients diagnosed with an incisional hernia. Adjusted odds for non-operative versus operative management and time to repair were queried. RESULTS: Of the 29,475 patients with an incisional hernia, 20,767 (70.5%) underwent non-operative management. In relation to private insurance, Medicaid (aOR 1.40, 95% CI 1.27-1.54), Medicare (aOR 1.53, 95% CI 1.42-1.65), and uninsured status (aOR 1.99, 95% CI 1.71-2.36) were independently associated with non-operative management. African American race (aOR 1.30, 95% CI 1.17-1.47) was associated with non-operative management while female sex (aOR 0.81, 95% CI 0.77-0.86) was predictive of elective repair. For patients who underwent elective repair, both Medicare (aOR 1.40, 95% CI 1.18-1.66) and Medicaid (aOR 1.49, 95% CI 1.29-1.71) insurance, but not race, were predictive of delayed repair (>90 days after diagnosis). CONCLUSIONS: Sex, race, and insurance status influence incisional hernia management. Development of evidence-based management guidelines may help to ensure equitable care.
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Hernia Ventral , Hernia Incisional , Adulto , Humanos , Femenino , Anciano , Estados Unidos , Medicare , Hernia Incisional/cirugía , Estudios Retrospectivos , Medicaid , Factores Socioeconómicos , Hernia Ventral/cirugíaRESUMEN
Rabbit antithymocyte globulin is a lymphocytedepleting agent commonly used as induction therapy in kidney transplants. Although its use is generally safe and well tolerated, serious side effects can occur. Here, we describe a case of a severe immune complex hypersensitivity reaction with disseminated intravascular coagulation in response to rabbit antithymocyte globulin infusion. Immediate treatment required return to the operating room, massive transfusion of blood products, and plasmapheresis. The patient's posttransplant course was significant for volume overload, prolonged respiratory failure, and delayed graft function that required hemodialysis, but within 10 weeks the patient had made a full recovery and kidney allograft function had returned to normal.
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Coagulación Intravascular Diseminada , Trasplante de Riñón , Suero Antilinfocítico , Coagulación Intravascular Diseminada/diagnóstico , Coagulación Intravascular Diseminada/tratamiento farmacológico , Coagulación Intravascular Diseminada/etiología , Rechazo de Injerto , Humanos , Inmunosupresores , Trasplante de Riñón/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of the study was to quantify the risk of incarceration of incisional hernias. BACKGROUND: Operative repair is the definitive treatment for incisional ventral hernias but is often deferred if the perceived risk of elective operation is elevated secondary to comorbid conditions. The risk of incarceration during nonoperative management (NOM) factors into shared decision making by patient and surgeon; however, the incidence of acute incarceration remains largely unknown. METHODS: A retrospective analysis of adult patients with an International Classification of Diseases, Ninth Revision or Tenth Revision diagnosis of incisional hernia was conducted from 2010 to 2017 in 15 hospitals of a single healthcare system. The primary outcome was incarceration necessitating emergent operation. The secondary outcome was 30-, 90-, and 365-day mortality. Univariate and multivariate analyses were used to determine independent predictors of incarceration. RESULTS: Among 30,998 patients with an incisional hernia (mean age 58.1â±â15.9 years; 52.7% female), 23,022 (78.1%) underwent NOM of whom 540 (2.3%) experienced incarceration, yielding a 1- and 5-year cumulative incidence of 1.24% and 2.59%, respectively. Independent variables associated with incarceration included: age older than 40 years, female sex, current smoker, body mass index 30 or greater, and a hernia-related inpatient admission. All-cause mortality rates at 30, 90, and 365 days were significantly higher in the incarceration group at 7.2%, 10%, and 14% versus 1.1%, 2.3%, and 5.3% in patients undergoing successful NOM, respectively. CONCLUSIONS: Incarceration is an uncommon complication of NOM but is associated with a significant risk of death. Tailored decision making for elective repair and considering the aforementioned risk factors for incarceration provides an initial step toward mitigating the excess morbidity and mortality of an incarceration event.
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Hernia Ventral/complicaciones , Hernia Ventral/terapia , Hernia Incisional/complicaciones , Hernia Incisional/terapia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de RiesgoRESUMEN
AIM: The use of kidneys donated after circulatory death (DCD) provides an invaluable expansion of the organ supply for transplantation. Here, we investigated the effect of DCD on fibrotic changes on 1 1-year post 1-transplant surveillance kidney allograft biopsy. METHODS: Recipients of a deceased donor kidney transplant between 2013 and 2017 at a single institution, who survived 1 year and underwent surveillance biopsy, were included in the analysis (n = 333: 87 DCD kidneys, 246 kidneys donated after brain death [DBD]). Banff scores for interstitial fibrosis and tubular atrophy were summed as IFTA and compared between the groups. RESULTS: DCD and DBD groups were comparable for baseline characteristics. Delayed graft function was 39% in DCD versus 19% in DBD, P = .0002. Patient and graft survival were comparable for DCD and DBD cohorts. IFTA scores were higher in DCD compared to DBD (2.43±..13 vs. 2.01±..08, P = .0054). On multivariate analysis, the odds of IFTA > 2 in the DCD group was 2.5× higher (95%CI: 1.354.63) than in the DBD group. Within the DCD group, kidneys with IFTA > 2 had inferior 5-year graft survival (P = .037). CONCLUSION: Compared to DBD kidneys, DCD kidneys developed a greater degree of fibrotic changes on 1-year post-transplant surveillance biopsy, which affected graft longevity within the DCD cohort.
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Trasplante de Riñón , Obtención de Tejidos y Órganos , Aloinjertos , Biopsia , Muerte Encefálica , Muerte , Fibrosis , Supervivencia de Injerto , Humanos , Riñón , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Donantes de TejidosRESUMEN
BACKGROUND: Regulatory T cell (Treg) therapy is a promising approach to amelioration of allograft rejection and promotion of organ transplant tolerance. However, the fate of infused Treg, and how this relates to their therapeutic efficacy using different immunosuppressive regimens is poorly understood. Our aim was to analyze the tissue distribution, persistence, replicative activity and phenotypic stability of autologous, donor antigen alloreactive Treg (darTreg) in anti-thymocyte globulin (ATG)-lymphodepleted, heart-allografted cynomolgus monkeys. METHODS: darTreg were expanded ex vivo from flow-sorted, circulating Treg using activated donor B cells and infused posttransplant into recipients of major histocompatibility complex-mismatched heart allografts. Fluorochrome-labeled darTreg were identified and characterized in peripheral blood, lymphoid, and nonlymphoid tissues and the graft by flow cytometric analysis. RESULTS: darTreg selectively suppressed autologous T cell responses to donor antigens in vitro. However, following their adoptive transfer after transplantation, graft survival was not prolonged. Early (within 2 wk posttransplant; under ATG, tacrolimus, and anti-IL-6R) or delayed (6-8 wk posttransplant; under rapamycin) darTreg infusion resulted in a rapid decline in transferred darTreg in peripheral blood. Following their early or delayed infusion, labeled cells were evident in lymphoid and nonlymphoid organs and the graft at low percentages (<4% CD4+ T cells). Notably, infused darTreg showed reduced expression of immunoregulatory molecules (Foxp3 and CTLA4), Helios, the proliferative marker Ki67 and antiapoptotic Bcl2, compared with preinfusion darTreg and endogenous CD4+CD25hi Treg. CONCLUSIONS: Lack of therapeutic efficacy of infused darTreg in lymphodepleted heart graft recipients appears to reflect loss of a regulatory signature and proliferative and survival capacity shortly after infusion.
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Traslado Adoptivo , Suero Antilinfocítico/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis , Proliferación Celular , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Trasplante de Corazón , Activación de Linfocitos , Depleción Linfocítica , Linfocitos T Reguladores/trasplante , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Trasplante de Corazón/efectos adversos , Macaca fascicularis , Masculino , Fenotipo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factores de TiempoRESUMEN
The article describes and illustrates the surgical techniques and the post-operative imaging anatomy in liver transplantation. Special attention is paid to the variant vascular and biliary anatomy that are important for surgical planning. Considering the ever-growing number of liver transplants performed and the key role that imaging plays in the pre-operative planning and post-operative assessment, it is important for the radiologist to be familiar with the surgical techniques and the normal post-operative appearance in these patients.
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Sistema Biliar , Trasplante de Hígado , Diagnóstico por Imagen , Humanos , Hígado/diagnóstico por imagen , Hígado/cirugía , Donadores VivosRESUMEN
BACKGROUND: Incisional hernia develops in up to 20% of patients undergoing abdominal operations. We sought to identify characteristics associated with poor outcomes after acute incisional hernia incarceration. STUDY DESIGN: We performed a retrospective cohort study of adult patients with incisional hernias undergoing elective repair or with acute incarceration between 2010 and 2017. The primary end point was 30-day mortality. Logistic regression was used to determine adjusted odds associated with 30-day mortality. The American College of Surgeons Surgical Risk Calculator was used to estimate outcomes had these patients undergone elective repair. RESULTS: A total of 483 patients experienced acute incarceration; 30-day mortality was 9.52%. Increasing age (adjusted odds ratio 1.05; 95% CI, 1.02 to 1.08) and bowel resection (adjusted odds ratio 3.18; 95% CI, 1.45 to 6.95) were associated with mortality. Among those with acute incarceration, 231 patients (47.9%) had no documentation of an earlier surgical evaluation and 252 (52.2%) had been evaluated but had not undergone elective repair. Among patients 80 years and older, 30-day mortality after emergent repair was high (22.9%) compared with estimated 30-day mortality for elective repair (0.73%), based on the American College of Surgeons Surgical Risk Calculator. Estimated mortality was comparable with observed elective repair mortality (0.82%) in an age-matched cohort. Similar mortality trends were noted for patients younger than 60 years and aged 60 to 79 years. CONCLUSIONS: Comparison of predicted elective repair and observed emergent repair mortality in patients with acute incarceration suggests that acceptable outcomes could have been achieved with elective repair. Almost one-half of acute incarceration patients had no earlier surgical evaluation, therefore, targeted interventions to address surgical referral can potentially result in fewer incarceration-related deaths.
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Abdomen/cirugía , Herniorrafia , Hernia Incisional/mortalidad , Hernia Incisional/cirugía , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/cirugía , Enfermedad Aguda , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Innate immunity can initiate platelet activation during the development of thrombosis through a process, termed immunothrombosis. Neutrophils form neutrophil extracellular traps (NETs) that have been shown to interact directly with platelets and play pro-coagulant roles in a variety of infectious and sterile inflammatory settings. Hepatic surgical stress initiated by ischemia/reperfusion (I/R) injury has wide systemic consequences on distant organs. However, the mechanisms of this remote injury phenomenon are not well-understood. Here, we sought to determine the role of NETs in causing systemic immunothrombosis and distant organ injury following a local inflammatory insult with liver I/R. Postoperative thromboelastographic revealed that the speed of clot formation (alpha-angle) was significantly increased whereas time to clot formation (R-time) were decreased by in patients undergoing liver resection, indicating a hypercoagulable state after surgery. In mice subjected to liver I/R, circulating platelet activation and platelet-neutrophil aggregates were significantly increased. Injured distant organs such as the lung and kidney displayed NETs and platelet-rich micro-thrombi in the microvasculature following liver I/R. The immune-thrombi and organ damage were dramatically decreased when NETs were inhibited by DNase treatment. Depletion of Tlr4 on platelets limited NET-induced activation of platelets but had no effect on NET formation. Furthermore, platelet-specific TLR4 KO mice had significantly reduced distant organ injury with decreased circulating platelet activation, platelet-neutrophil aggregates following liver I/R in comparison to their control counterparts. These data establish that after an acute local inflammatory process, NET-activated platelets can lead to a systemic pro-coagulant state with resultant remote organ injury by immunothrombosis.
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Coagulación Sanguínea , Plaquetas/inmunología , Trampas Extracelulares/inmunología , Hepatectomía/efectos adversos , Neutrófilos/inmunología , Activación Plaquetaria , Daño por Reperfusión/inmunología , Trombosis/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Plaquetas/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Modelos Animales de Enfermedad , Trampas Extracelulares/metabolismo , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Neutrófilos/metabolismo , Arginina Deiminasa Proteína-Tipo 4/deficiencia , Arginina Deiminasa Proteína-Tipo 4/genética , Daño por Reperfusión/sangre , Transducción de Señal , Estrés Fisiológico , Trombosis/sangre , Receptor Toll-Like 4/deficiencia , Receptor Toll-Like 4/genética , Adulto JovenRESUMEN
Transplantation of kidneys from deceased donors with acute kidney injury (AKI) can expand the donor pool. We investigated the effect of donor AKI on renal function and chronic changes on protocol biopsies at 1-year post-transplant. Donor AKI was defined according to Acute Kidney Injury Network (AKIN) criteria. Between 2013 and 2017, 333 kidneys were transplanted and subsequently biopsied after 1 year. Fifty-three kidneys from AKI donors (AKIN stage I n = 42, stage II n = 8, stage III n = 3) were compared to 280 kidneys from non-AKI donors. At 1-year follow-up, patient and graft survival were comparable. Donor AKI was not predictive of IFTA (Banff interstitial fibrosis plus tubular atrophy scores) at 1-year post-transplant biopsy (2.10 ± 1.28 in AKI, 2.09 ± 1.22 in non-AKI, P = .95). Donor AKI was also not associated with progression of IFTA from 3 to 12 months (P = .69), or inferior glomerular filtration rate (eGFR, P = .94). In a multivariate analysis, the odds of IFTA >2 were comparable between AKI and non-AKI groups. In conclusion, the transplantation of kidneys from donors with predominantly stage I AKI results in comparable function and degree of fibrosis on protocol biopsies 1-year post-transplant. Selected grafts from donors with AKI are a valuable tool for expanding the donor pool for kidney transplantation.
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Lesión Renal Aguda , Funcionamiento Retardado del Injerto , Lesión Renal Aguda/etiología , Aloinjertos , Funcionamiento Retardado del Injerto/etiología , Fibrosis , Supervivencia de Injerto , Humanos , Riñón , Estudios Retrospectivos , Donantes de TejidosRESUMEN
Neutrophil infiltration and neutrophil extracellular traps (NET) in solid cancers are associated with poorer prognosis, but the mechanisms are incompletely understood. We hypothesized that NETs enhance mitochondrial function in tumor cells, providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis, and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC1α, TFAM, and NRF-1. In vitro, cancer cells treated with NETs upregulated mitochondrial biogenesis-associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential, and increased the oxygen consumption rate. Furthermore, NETs increased cancer cells' expression of fission and fusion-associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase released from NETs activated TLR4 on cancer cells, leading to PGC1α upregulation, increased mitochondrial biogenesis, and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression. SIGNIFICANCE: Neutrophils through the release of NETs facilitate the growth of stressed cancer cells by altering their bioenergetics, the inhibition of which induces cell death.
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Proliferación Celular/fisiología , Trampas Extracelulares/fisiología , Homeostasis/fisiología , Mitocondrias/fisiología , Neutrófilos/fisiología , Adenosina Trifosfato/metabolismo , Animales , Biomarcadores/metabolismo , Línea Celular , Línea Celular Tumoral , ADN Mitocondrial/metabolismo , Trampas Extracelulares/metabolismo , Células HCT116 , Humanos , Elastasa de Leucocito/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Infiltración Neutrófila/fisiología , Neutrófilos/metabolismoRESUMEN
BACKGROUND: The Risk Analysis Index (RAI) for frailty is a rapid survey for comorbidities and performance status, which predicts mortality after general surgery. We aimed to validate the RAI in predicting outcomes after hepatopancreatobiliary surgery. METHODS: Associations of RAI, determined in 162 patients prior to undergoing hepatopancreatobiliary surgery, with prospectively collected 30-day post-operative outcomes were analyzed with multivariate logistic and linear regression. RESULTS: Patients (age 62 ± 14, 51% female) had a median RAI of 7, range 0-25. With every unit increase in RAI, length of stay increased by 5% (95% CI: 2-7%), odds of ICU admission increased by 10% (0-20%), ICU length of stay increased by 21% (9-34%), and odds of discharge to a nursing facility increased by 8% (0-17%) (all P < 0.05). Particularly in patients who suffered a first post-operative complication, RAI was associated with additional complications (1.6 unit increase in Comprehensive Complication Index per unit increase in RAI, P = 0.002). In a direct comparison in a subset of 74 patients, RAI and the ACS-NSQIP Risk Calculator performed comparably in predicting outcomes. CONCLUSION: While RAI and ACS-NSQIP Risk Calculator comparatively predicted short-term outcomes after HPB surgery, RAI has been specifically designed to identify frail patients who can potentially benefit from preoperative prehabilitation interventions.
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Técnicas de Apoyo para la Decisión , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Fragilidad/diagnóstico , Complicaciones Posoperatorias/etiología , Anciano , Procedimientos Quirúrgicos del Sistema Biliar/efectos adversos , Toma de Decisiones Clínicas , Femenino , Anciano Frágil , Fragilidad/complicaciones , Hepatectomía/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Pancreatectomía/efectos adversos , Pancreaticoduodenectomía/efectos adversos , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high-fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4-/- ), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. CONCLUSION: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).
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Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Animales , Biomarcadores/metabolismo , Biopsia con Aguja , Carcinoma Hepatocelular/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Pronóstico , Distribución Aleatoria , Medición de RiesgoRESUMEN
The increasing prevalence of obesity has made nonalcoholic fatty liver disease (NAFLD) the most common chronic liver disease. As a consequence, NAFLD and especially its inflammatory form nonalcoholic steatohepatitis (NASH) are the fastest increasing etiology of end-stage liver disease and hepatocellular carcinoma. Physical inactivity is related to the severity of fatty liver disease irrespective of body weight, supporting the hypothesis that increasing physical activity through exercise can improve fatty liver disease. This review summarizes the evidence for the effects of physical exercise on NAFLD and NASH. Several clinical trials have shown that both aerobic and resistance exercise reduce the hepatic fat content. From clinical and basic scientific studies, it is evident that exercise affects fatty liver disease through various pathways. Improved peripheral insulin resistance reduces the excess delivery of free fatty acids and glucose for free fatty acid synthesis to the liver. In the liver, exercise increases fatty acid oxidation, decreases fatty acid synthesis, and prevents mitochondrial and hepatocellular damage through a reduction of the release of damage-associated molecular patterns. In conclusion, physical exercise is a proven therapeutic strategy to improve fatty liver disease.
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Terapia por Ejercicio , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Metabolismo Energético , Humanos , Insulina/metabolismo , Metabolismo de los Lípidos , Enfermedad del Hígado Graso no Alcohólico/terapiaRESUMEN
BACKGROUND & AIMS: Neutrophils and liver sinusoidal endothelial cells (LSECs) both contribute to sterile inflammatory injury during ischemia/reperfusion (I/R), a well-known liver surgical stress. Interleukin-33 (IL-33) has been shown to drive neutrophil infiltration during inflammatory responses through its receptor ST2. We recently reported that infiltrating neutrophils form neutrophil extracellular traps (NETs), which exacerbate sterile inflammatory injury in liver I/R. Here, we sought to determine the role of IL-33 in NET formation during liver sterile inflammation. METHODS: Evaluation of IL-33 forming NETs was investigated using a partial liver I/R model to generate sterile injury in healthy WT, IL-33 and ST2 knockouts. Serum levels of IL-33 and myeloperoxidase (MPO)-DNA complex were measured in both humans and mice after the first surgery. Liver damage was assessed. Mouse neutrophil depletion was performed by intraperitoneal injection of anti-Ly6G antibody before I/R. RESULTS: Patients undergoing liver resection showed a significant increase in serum IL-33 compared to healthy volunteers. This coincided with higher serum MPO-DNA complexes. NET formation was decreased in IL-33 and ST2 knockout mice compared with control mice, after liver I/R. IL-33 or ST2 deficiency protected livers from I/R injury, whereas rIL-33 administration during I/R exacerbated hepatotoxicity and systemic inflammation. In vitro, IL-33 is released from LSECs to promote NET formation. IL-33 deficient LSECs failed to induce NETs. ST2 deficient neutrophils limited their capacity to form NETs in vitro and adoptive transfer of ST2 knockout neutrophils to neutrophil-depleted WT mice significantly decreased NET formation. CONCLUSIONS: Data establish that IL-33, mainly released from LSECs, causes excessive sterile inflammation after hepatic I/R by inducing NET formation. Therapeutic targeting of IL-33/ST2 might extend novel strategies to minimize organ damage in various clinical settings associated with sterile inflammation. LAY SUMMARY: Liver ischemia and reperfusion injury results in the formation of neutrophil extracellular traps, which contribute to organ damage in liver surgeries. Herein, we show that IL-33 is released from liver sinusoidal endothelial cells to promote NET formation during liver I/R, which exacerbates inflammatory cascades and sterile inflammation.
RESUMEN
The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and up-regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC-1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC-1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine-induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll-like receptor-9. This binding leads to activation of p38 and subsequent phosphorylation of PGC-1α, with resultant up-regulation of mitochondrial biogenesis. CONCLUSION: Taken together, our findings suggest that during hypoxia HMGB1 up-regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (Hepatology 2017;66:182-197).
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Carcinoma Hepatocelular/genética , Proteína HMGB1/genética , Neoplasias Hepáticas/genética , Biogénesis de Organelos , Receptor Toll-Like 9/metabolismo , Animales , Carcinoma Hepatocelular/patología , Hipoxia de la Célula , Supervivencia Celular , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Distribución Aleatoria , Transducción de Señal , Activación Transcripcional , Células Tumorales CultivadasRESUMEN
BACKGROUND: The pig-to-non-human primate model is the standard choice for in vivo studies of organ and cell xenotransplantation. In 1998, Lambrigts and his colleagues surveyed the entire world literature and reported all experimental studies in this model. With the increasing number of genetically engineered pigs that have become available during the past few years, this model is being utilized ever more frequently. METHODS: We have now reviewed the literature again and have compiled the data we have been able to find for the period January 1, 1998 to December 31, 2013, a period of 16 yr. RESULTS: The data are presented for transplants of the heart (heterotopic and orthotopic), kidney, liver, lung, islets, neuronal cells, hepatocytes, corneas, artery patches, and skin. Heart, kidney, and, particularly, islet xenograft survival have increased significantly since 1998. DISCUSSION: The reasons for this are briefly discussed. A comment on the limitations of the model has been made, particularly with regard to those that will affect progression of xenotransplantation toward the clinic.