RESUMEN
Injury and growth stimulation both remarkably increase the hepatic expression of Gadd45ß. This contrasts with expression in liver cancer, where promoter methylation frequently silences Gadd45ß, due to a suppressive function that is often proapoptotic. In normal hepatocytes, Gadd45ß facilitates cell survival, growth, and proliferation. Gadd45ß binds MKK7-downstream of TNFα and its receptors-to prevent this kinase from activating JNK2. Hence, the Gadd45ß-/- genotype increases cell injury and decreases cell proliferation during liver regeneration (compensatory growth and proliferation). Liver hyperplasia (de novo growth and proliferation) is an alternate form of growth, caused by drugs that activate the nuclear receptor, CAR. As in regeneration, the Gadd45ß-/- genotype considerably slows growth during hyperplasia. However, there is no injury and the slowing occurs because Gadd45ß normally binds to CAR and activates its transcriptional stimulation. Thus, Gadd45ß protects the liver through two entirely different processes: Binding MKK7 to block damaging signal transduction, or binding CAR to coactivate anabolic transcription.
Asunto(s)
Antígenos de Diferenciación , Hígado , Antígenos de Diferenciación/genética , Humanos , Hiperplasia/metabolismo , Hiperplasia/patología , Hígado/metabolismo , Regeneración Hepática/genética , Transducción de Señal/fisiologíaRESUMEN
Nkx2.9 is a member of the NK homeobox family and resembles Nkx2.2 both in homology and expression pattern. However, while Nkx2.2 is required for development of serotonergic neurons, the role of Nkx2.9 in the mid-hindbrain region is still ill-defined. We have previously shown that Nkx2.9 expression is downregulated upon loss of En1 during development. Here, we determined whether mdDA neurons require Nkx2.9 during their development. We show that Nkx2.9 is strongly expressed in the IsO and in the VZ and SVZ of the embryonic midbrain, and the majority of mdDA neurons expressed Nkx2.9 during their development. Although the expression of Dat and Cck are slightly affected during development, the overall development and cytoarchitecture of TH-expressing neurons is not affected in the adult Nkx2.9-depleted midbrain. Transcriptome analysis at E14.5 indicated that genes involved in mid- and hindbrain development are affected by Nkx2.9-ablation, such as Wnt8b and Tph2. Although the expression of Tph2 extends more rostral into the isthmic area in the Nkx2.9 mutants, the establishment of the IsO is not affected. Taken together, these data point to a minor role for Nkx2.9 in mid-hindbrain patterning by repressing a hindbrain-specific cell-fate in the IsO and by subtle regulation of mdDA neuronal subset specification.
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Neuronas Dopaminérgicas/química , Perfilación de la Expresión Génica/métodos , Proteínas de Homeodominio/genética , Rombencéfalo/crecimiento & desarrollo , Factores de Transcripción/genética , Animales , Tipificación del Cuerpo , Diferenciación Celular , Regulación del Desarrollo de la Expresión Génica , Mesencéfalo/química , Mesencéfalo/citología , Ratones , Rombencéfalo/química , Análisis de Secuencia de ARNRESUMEN
BACKGROUND & AIMS: Upon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about the mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms. METHODS: We used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration. We analyzed zebrafish with disruptions of the histone deacetylase 1 gene (hdac1) or exposed to MS-275 (an inhibitor of Hdac1, Hdac2, and Hdac3). We also analyzed zebrafish with mutations in sox9b, fbxw7, kdm1a, and notch3. Zebrafish larvae were collected and analyzed by whole-mount immunostaining and in situ hybridization; their liver tissues were collected for quantitative reverse transcription polymerase chain reaction. We studied mice in which hepatocyte-specific deletion of ß-catenin (Ctnnb1flox/flox mice injected with Adeno-associated virus serotype 8 [AAV8]-TBG-Cre) induces differentiation of LPCs into hepatocytes after a choline-deficient, ethionine-supplemented (CDE) diet. Liver tissues were collected and analyzed by immunohistochemistry and immunoblots. We performed immunohistochemical analyses of liver tissues from patients with compensated or decompensated cirrhosis or acute on chronic liver failure (n = 15). RESULTS: Loss of Hdac1 activity in zebrafish blocked differentiation of LPCs into hepatocytes by increasing levels of sox9b mRNA and reduced differentiation of LPCs into BECs by increasing levels of cdk8 mRNA, which encodes a negative regulator gene of Notch signaling. We identified Notch3 as the receptor that regulates differentiation of LPCs into BECs. Loss of activity of Kdm1a, a lysine demethylase that forms repressive complexes with Hdac1, produced the same defects in differentiation of LPCs into hepatocytes and BECs as observed in zebrafish with loss of Hdac1 activity. Administration of MS-275 to mice with hepatocyte-specific loss of ß-catenin impaired differentiation of LPCs into hepatocytes after the CDE diet. HDAC1 was expressed in reactive ducts and hepatocyte buds of liver tissues from patients with cirrhosis. CONCLUSIONS: Hdac1 regulates differentiation of LPCs into hepatocytes via Sox9b and differentiation of LPCs into BECs via Cdk8, Fbxw7, and Notch3 in zebrafish with severe hepatocyte loss. HDAC1 activity was also required for differentiation of LPCs into hepatocytes in mice with liver injury after the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases.
Asunto(s)
Conductos Biliares/enzimología , Diferenciación Celular , Proliferación Celular , Quinasa 8 Dependiente de Ciclina/metabolismo , Hepatocitos/enzimología , Histona Desacetilasa 1/metabolismo , Regeneración Hepática , Hígado/enzimología , Factor de Transcripción SOX9/metabolismo , Células Madre/enzimología , Proteínas de Pez Cebra/metabolismo , Insuficiencia Hepática Crónica Agudizada/enzimología , Insuficiencia Hepática Crónica Agudizada/patología , Animales , Conductos Biliares/patología , Deficiencia de Colina/genética , Deficiencia de Colina/metabolismo , Deficiencia de Colina/patología , Quinasa 8 Dependiente de Ciclina/genética , Modelos Animales de Enfermedad , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Hepatocitos/patología , Histona Desacetilasa 1/genética , Humanos , Hígado/patología , Cirrosis Hepática/enzimología , Cirrosis Hepática/patología , Ratones Noqueados , Mutación , Receptor Notch3/genética , Receptor Notch3/metabolismo , Factor de Transcripción SOX9/genética , Transducción de Señal , Células Madre/patología , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/ß-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific ß-catenin knockout mice and wild-type littermates were subjected to cholestatic injury through bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Intriguingly, knockout mice exhibit a dramatic protection from liver injury, fibrosis, and atypical ductular proliferation, which coincides with significantly decreased total hepatic bile acids (BAs). This led to the discovery of a role for ß-catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that ß-catenin functions as both an inhibitor of nuclear translocation and a nuclear corepressor through formation of a physical complex with FXR. Loss of ß-catenin expedited FXR nuclear localization and FXR/retinoic X receptor alpha association, culminating in small heterodimer protein promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of ß-catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of ß-catenin expression during cholestatic injury reduces ß-catenin/FXR complex activation of FXR to decrease total BA and alleviate hepatic injury. CONCLUSION: We have identified an FXR/ß-catenin interaction whose modulation through ß-catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (Hepatology 2018;67:955-971).
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Colestasis/metabolismo , Hígado/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , beta Catenina/metabolismo , Animales , Hígado/patología , Ratones , Ratones Noqueados , Transducción de SeñalRESUMEN
BACKGROUND: Differentiating between malignant and benign biliary lesions is critical in clinical practice but is difficult. OBJECTIVE: To systematically evaluate the diagnostic performance of single-operator peroral cholangioscopy on indeterminate biliary lesions. DESIGN: A systematic review and meta-analysis. PATIENTS: Patients with indeterminate biliary lesions or equivocal ERCP findings. MAIN OUTCOME MEASUREMENTS: The diagnostic performance of single-operator peroral cholangioscopy on indeterminate biliary lesions. The area under the summary receiver-operating characteristic curve was used as the main indicator for the overall diagnostic performance of single-operator peroral cholangioscopy visual impression (VI) and SpyBite biopsy (SB). The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were also synthesized. RESULTS: A total of 8 studies met the inclusion criteria, involving 335 patients who had data on VI and 337 who had data on SB. The area under the curve values on the summary receiver-operating characteristic curve of single-operator peroral cholangioscopy VI and SB were 0.94 (95% confidence interval [CI], 0.92-0.96) and 0.93 (95% CI, 0.90-0.95) respectively. The combined sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 90% (95% CI, 73%-97%), 87% (95% CI, 76%-94%), 7.1 (95% CI, 3.8-13.3), 0.12 (95% CI, 0.04-0.33) for VI and 69% (95% CI, 57%-79%), 98% (95% CI, 92%-99%), 30.1 (95% CI, 8.5-106.9), and 0.32 (95% CI, 0.23-0.44) for SB, respectively. LIMITATIONS: Small number of included studies; comparison with ERCP could not be made. CONCLUSION: Single-operator peroral cholangioscopy is a good tool for differentiating malignant and benign biliary lesions. VI is useful for detecting malignant lesion, whereas SB is better at confirming a malignant diagnosis, but VI is not perfect in excluding biliary cancer, nor is SB, and their negative results should be interpreted with caution.
Asunto(s)
Enfermedades de los Conductos Biliares/diagnóstico , Endoscopía del Sistema Digestivo/métodos , Neoplasias de los Conductos Biliares/diagnóstico , Diagnóstico Diferencial , Humanos , Sensibilidad y EspecificidadRESUMEN
Ketamine is a commonly used pediatric anesthetic, but it might affect development, or even induce neurotoxicity in the neonatal brain. We have used an in vivo neonatal mouse model to induce ketamine-related neurotoxicity in the hippocampus, and found that miR-34c, a microRNA associated with pathogenesis of Alzheimer's disease, was significantly upregulated during ketamine-induced hippocampal neurodegeneration. Functional assay of silencing miR-34c demonstrated that downregulation of miR-34c activated PKC-ERK pathway, upregulated anti-apoptotic protein BCL2, and ameliorated ketamine-induced apoptosis in the hippocampus. Cognitive examination with the Morris water maze test showed that ketamine-induced memory impairment was significantly improved by miR-34c downregulation. Thus, miR-34c is important in regulating ketamine-induced neurotoxicity in hippocampus.
Asunto(s)
Apoptosis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Ketamina/toxicidad , MicroARNs/metabolismo , Animales , Animales Recién Nacidos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , Oligonucleótidos Antisentido/metabolismo , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a multicellular etiology. METHODS: Progressive changes in the rat carbon tetrachloride model were studied by deep RNA sequencing and genome-wide chromatin immunoprecipitation sequencing analysis of transcription factor (TF) binding and chromatin modification. Studies compared decompensated cirrhosis with liver failure after 26 weeks of treatment with earlier compensated cirrhosis and with additional rat models of chronic fibrosis. Finally, to resolve cell-specific responses and intercellular signaling, we compared transcriptomes of liver, nonparenchymal, and inflammatory cells. RESULTS: HNF4α was significantly lower in 26-week cirrhosis, part of a general reduction of TFs that regulate metabolism. Nevertheless, increased binding of HNF4α contributed to strong activation of major phenotypic genes, whereas reduced binding to other genes had a moderate phenotypic effect. Decreased Hnf4a expression was the combined effect of STAT3 and nuclear factor kappa B (NFκB) activation, which similarly reduced expression of other metabolic TFs. STAT/NFκB also induced de novo expression of Osmr by hepatocytes to complement induced expression of Osm by nonparenchymal cells. CONCLUSIONS: Liver decompensation by inflammatory STAT3 and NFκB signaling was not a direct consequence of progressive cirrhosis. Despite significant reduction of Hnf4a expression, residual levels of this abundant TF still stimulated strong new gene expression. Reduction of HNF4α was part of a broad hepatocyte transcriptional response to inflammation.
Asunto(s)
Factor Nuclear 4 del Hepatocito , Fallo Hepático , Animales , Ratas , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Hepatocitos/metabolismo , Cirrosis Hepática/patología , Fallo Hepático/metabolismoRESUMEN
BACKGROUND AND AIMS: Positron emission tomography with computed tomography (PET/CT) has been used to detect metastasis in the diagnosis of esophageal adenocarcinoma (EAC). However, the utility of PET/CT to assess primary tumor for endoscopic resectability and prognosis in early EAC remains unclear. We conducted a retrospective study to determine the association of PET/CT findings with histopathological tumor invasion depth and survival outcomes. METHODS: EAC patients who underwent PET/CT followed by endoscopic mucosal resection (EMR) were included. Pathology on EMR and survival outcomes from a prospectively maintained database was retrieved. Two radiologists independently reviewed the PET/CT using the following parameters: detection of malignancy, fluorodeoxyglucose (FDG) uptake intensity, FDG focality, FDG eccentricity, esophageal thickness, maximal standard uptake value (SUVmax), and SUVmax ratio (lesion/liver). RESULTS: There were 72 eligible patients: 42 (58.3%) had T1a lesions, and 30 (41.7%) had ≥ T1b. Only SUVmax ratio was associated with tumor invasion depth (odds ratio=2.77, 95% confidence interval 1.26-7.73, P=0.0075). Using a cut-off of 1.48, the sensitivity and specificity of SUVmax ratio for identification of T1a lesions were 43.3% and 80.9%, respectively. Adjusting the SUVmax ratio to 2.14, 16.7% (5/30) of ≥ T1b patients were identified without any false-positive cases. Multivariate analysis showed SUVmax ratio, Charlson comorbidity index, and esophagectomy were independent predictors for survival. CONCLUSIONS: SUVmax ratio (lesion/liver) is more accurate in predicting endoscopic resectability and mortality for EAC than other PET/CT parameters and appears promising as a useful adjunct to the current diagnostic work-up.
Asunto(s)
Adenocarcinoma/diagnóstico , Adenocarcinoma/cirugía , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/cirugía , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Adenocarcinoma/mortalidad , Anciano , Neoplasias Esofágicas/mortalidad , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Injury and growth stimulation both remarkably increase the hepatic expression of Gadd45ß. In liver cancer, promoter methylation frequently silences Gadd45ß, demonstrating due to a suppressive function that is often proapoptotic. This contrasts with normal hepatocytes, where Gadd45ß facilitates cell survival, growth, and proliferation. Gadd45ß binds MKK7-downstream of TNFα and its receptors-to prevent this kinase from activating JNK2. Hence, the Gadd45b-/- genotype increases cell injury and decreases cell proliferation during liver regeneration (i.e., compensatory growth and proliferation). Liver hyperplasia (i.e., de novo growth and proliferation) is an alternate form of growth, caused by drugs that activate the nuclear receptor, CAR. As in regeneration, the Gadd45b-/- genotype considerably slows growth during hyperplasia. However, there is no injury and the slowing occurs because Gadd45ß normally binds to CAR and activates its transcriptional stimulation. Thus, Gadd45ß protects the liver through two entirely different processes: binding MKK7 to block damaging signal transduction or binding CAR to coactivate anabolic transcription.
Asunto(s)
Antígenos de Diferenciación/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , MAP Quinasa Quinasa 7/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal , Antígenos de Diferenciación/genética , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Puntos de Control del Ciclo Celular , Proliferación Celular , Receptor de Androstano Constitutivo , Regulación de la Expresión Génica , Hepatocitos/citología , Humanos , Hígado/citología , Regeneración Hepática/genética , MAP Quinasa Quinasa 7/genética , Regiones Promotoras Genéticas , Unión Proteica , Receptores Citoplasmáticos y Nucleares/genética , Transcripción GenéticaRESUMEN
BACKGROUND: Transversus abdominis plane block (TAPB) is a block of the abdominal afferent nerve fibers between the internal oblique muscle and the transverse abdominal muscle achieved with local anesthetics. It can effectively block the conduction of the anterior nerve of the abdominal wall and exert a good analgesic effect. However, the effect of combining the block with remimazolam on anesthesia in patients undergoing gastrointestinal tumor surgery is still unclear. AIM: To examine the effects of combining TAPB with remimazolam on the stress response and postoperative recovery of gastrointestinal tumor surgery patients. METHODS: A retrospective analysis was conducted on the clinical data of 102 individuals diagnosed with gastrointestinal malignancies who underwent laparoscopic surgery under general anesthesia between April 2020 and June 2023. The patients were categorized into a control group (n = 51), receiving remimazolam for general anesthesia, and an observation group (n = 51), receiving TAPB combined with remimazolam for general anesthesia. A comparison was made between both groups in terms of hemodynamic parameters, stress markers, pain levels, recovery quality, analgesic effects, and adverse reactions during the perioperative period. RESULTS: The observation group had significantly higher heart rates at time points 1 min after induction and upon leaving the operating room than the control group (P < 0.05). The mean arterial pressure at time point T1 in the observation group was significantly higher than that in the control group (P < 0.05). Five minutes after extubation, the levels of the hormones adrenaline and noradrenaline in the observation group were considerably lower than those in the control group (P < 0.05). At 12 h, 24 h, and 48 h following surgery, the visual analog scale scores of the observation group were considerably lower than those of the control group (P < 0.05). The observation group had shorter awakening and extubation times and lower Riker sedation-agitation scale scores than the control group (P < 0.05). The observation group exhibited considerably fewer effective pump presses, lower fentanyl dosages, and lower incidences of rescue analgesia within 24 h following surgery than the control group (P < 0.05). CONCLUSION: The application effect of TAPB combined with remimazolam general anesthesia in anesthesia of patients undergoing gastrointestinal tumor surgery is good, which is helpful to promote faster recovery after operation.
RESUMEN
Cholangiocarcinoma (CC) is a rare primary malignancy of the biliary tract with a dismal prognosis. Curative resection can only be applied to a small proportion of early diagnosed patients. Palliative biliary drainage by either percutaneous or endoscopic insertion of endoprostheses improves quality-of-life by reducing pruritis, cholangitis, and pain, but has been reported to improve survival time only slightly. Photodynamic therapy (PDT) is a relatively new local, minimally invasive palliative strategy for unresectable CC. PDT uses a photosensitive molecule that accumulates in proliferating tissue such as tumors. Activation of the photosensitizer by use of light of a specific wavelength generates reactive oxygen species leading to selective tumor-cell death. After initial feasibility studies and promising prospective phase II studies, results from two prospective randomized controlled trials comparing PDT after endoprostheses insertion with endoprostheses alone for patients with unresectable CC have been published. One study resulted in dramatically prolonged median survival in the PDT group (493 days) compared with the non-PDT group (98 days) (P < 0.0001), and significantly improved performance status (PS) in the PDT group. A second study with high baseline patients' PS confirmed the benefit of PDT for survival (630 days in the PDT group compared with 210 days for endoprostheses alone, P < 0.01). The procedures were generally well tolerated. PDT has also been reported to have a favorable outcome as adjuvant and neoadjuvant therapy for CC. Although accumulated data and local expertise are limited, PDT can be regarded as a standard palliative therapy for unresectable CC.
Asunto(s)
Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Neoplasias de los Conductos Biliares/sangre , Neoplasias de los Conductos Biliares/clasificación , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/cirugía , Bilirrubina/sangre , Colangiocarcinoma/sangre , Colangiocarcinoma/clasificación , Colangiocarcinoma/mortalidad , Colangiocarcinoma/cirugía , Éter de Dihematoporfirina/uso terapéutico , Humanos , Cuidados Paliativos , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Stents , Resultado del TratamientoRESUMEN
OBJECTIVES: Recent studies have demonstrated high esophageal eosinophil counts in patients with GERD similar to eosinophilic esophagitis (EoE) yet the frequency of esophageal eosinophilia in GERD is unknown. Our aim was to determine the prevalence of dense esophageal eosinophilia in patients with Barrett's esophagus as a manifestation of GERD. METHODS: The Mayo Clinic pathology database was reviewed for patients diagnosed with Barrett's esophagus from January to December 2008 with squamous mucosa obtained during endoscopic surveillance. Clinical, endoscopic, and histologic findings were reviewed. Patients with ≥15 eosinophils per high powered field were identified and compared to those without esophageal eosinophilia. RESULTS: Two hundred patients with Barrett's esophagus and squamous tissue obtained at the time of biopsy were identified. Fourteen of the 200 patients (7%) had ≥15 eosinophils per high powered field. Demographics, symptoms, and proton pump inhibitor therapies were similar between those with and without esophageal eosinophilia. Endoscopic features suggestive of EoE were found in the squamous mucosa of 2 patients with and 7 patients without esophageal eosinophilia. Use of photodynamic, radiofrequency ablation, or monopolar electrocoagulation therapy for ablation of Barrett's mucosa was not associated with a higher rate of esophageal eosinophilia. Basal cell hyperplasia, papillary elongation, and spongiosis occurred frequently in association with esophageal eosinophilic infiltration. CONCLUSIONS: High esophageal eosinophil counts were found in 7% of this cohort of 200 patients with Barrett's esophagus and likely underestimates prevalence. The finding of esophageal eosinophilia in this cohort was independent of proton pump inhibitor use, features of EoE, or endoscopic therapy for Barrett's esophagus. Further studies are needed to assess if these findings are applicable to all patients with GERD.
Asunto(s)
Esófago de Barrett/patología , Eosinófilos/patología , Esófago/patología , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/tratamiento farmacológico , Esófago de Barrett/cirugía , Biopsia con Aguja , Recuento de Células , Esofagitis Eosinofílica/patología , Esofagoscopía , Femenino , Reflujo Gastroesofágico/patología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
UNLABELLED: Sirolimus is used in patients with renal insufficiency after liver transplantation (LT) and especially in those with calcineurin inhibitor (CNI)-associated nephrotoxicity. We conducted a systematic review of all randomized controlled trials and observational studies to test the hypothesis that the use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency [glomerular filtration rate (GFR) < 60 mL/minute or creatinine level ≥ 1.5 mg/dL]. We performed a search of all major databases, conference proceedings, and relevant journals through December 2009 and contacted content experts, corresponding authors, and the pharmaceutical manufacturer. A random effects model was used to determine the pooled estimate of the change in renal function and pooled risk estimates of adverse events that may be associated with sirolimus-based therapy at 1 year. Eleven studies (three randomized controlled trials and eight observational studies) met the final inclusion criteria. A nonsignificant improvement of 3.38 mL/minute [95% confidence interval (CI) = -2.93 to 9.69] was observed in methodologically sound observational studies and controlled trials reporting the primary outcome. In controlled trials, baseline GFR >50 mL/min sirolimus use was associated with an improvement of 10.35 mL/minute (95% CI = 3.98-16.77) in GFR or creatinine clearance. Sirolimus was not significantly associated with death [relative risk (RR) = 1.12, 95% CI = 0.66-1.88] or graft failure (RR = 0.80, 95% CI = 0.45-1.41), although reporting was incomplete. It was associated with a statistically significant risk of infection (RR = 2.47, 95% CI = 1.14-5.36), rash (RR = 7.57, 95% CI = 1.75-32.70), ulcers (RR = 7.44, 95% CI = 2.03-27.28), and discontinuation of therapy (RR = 3.61, 95% CI = 1.32-9.89). CONCLUSION: Conversion to sirolimus from CNIs is associated with a nonsignificant improvement in renal function in LT recipients with renal insufficiency, although the results are limited by heterogeneity, a risk of bias, and a lack of standardized reporting.
Asunto(s)
Inmunosupresores/efectos adversos , Trasplante de Hígado/efectos adversos , Insuficiencia Renal/inducido químicamente , Sirolimus/efectos adversos , Adulto , Inhibidores de la Calcineurina , Creatinina/metabolismo , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: Esophagectomy is usually recommended for patients with submucosal esophageal adenocarcinoma (T1b EAC) because of the potential for lymph node metastasis (LNM). Endoscopic management often differs based on the risk of metastasis. There is limited information on the difference in outcomes for T1b-EAC with and without esophagectomy. OBJECTIVES: To investigate (1) the outcomes of T1b EAC treatments with and without esophagectomy and (2) the percentage of LNM at esophagectomy for T1b-EAC. DESIGN: Retrospective cohort. SETTING: A tertiary Barrett's esophagus unit. PATIENTS: Sixty-eight T1b EAC patients based on EMR histology. INTERVENTIONS: Esophagectomy and endoscopic therapies. MAIN OUTCOME MEASUREMENTS: Survival duration and mortality rate. RESULTS: A total of 68 patients had T1b EAC; cumulative mortality rate was 30.9% and median survival duration was 39.5 months. Thirty-nine underwent esophagectomy and 29 did not. Among patients who underwent esophagectomy, 13 (33.3%) had LNM, and the mortality rate was 50.0% and 11.1% for those with and without LNM, respectively (P < .01). For those with and without esophagectomy, the cumulative mortality rates were 25.6% and 37.9%, and median survival duration was 48.9 and 34.8 months, respectively. There was no statistical difference in Charlson comorbidity index, number of EMRs, mortality rate, or survival duration. In Cox proportional hazard model analysis, the hazard ratio for esophagectomy was 0.5 (P = .21). LIMITATIONS: Retrospective, nonrandomized small sample size cohort. CONCLUSION: Among the patients with T1b EAC found in EMR specimens who underwent esophagectomy, one third had regional LNM. In our small series, patients who underwent esophagectomy did not have a significantly different survival duration from that of those who did not, indicating that these patients may have similar outcomes [corrected].
Asunto(s)
Adenocarcinoma/diagnóstico , Antineoplásicos/uso terapéutico , Neoplasias Esofágicas/diagnóstico , Esofagectomía/métodos , Estadificación de Neoplasias , Adenocarcinoma/terapia , Anciano , Biopsia con Aguja Fina , Diagnóstico Diferencial , Endosonografía , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Minnesota/epidemiología , Tomografía de Emisión de Positrones , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Resultado del TratamientoRESUMEN
RATIONALE: Studies examining survival outcomes after in-hospital cardiopulmonary arrest (CPA) among intensive care unit (ICU) patients requiring medications for hemodynamic support are limited. OBJECTIVES: To examine outcomes of ICU patients who received cardiopulmonary resusitation. METHODS: We identified 49,656 adult patients with a first CPA occurring in an ICU between January 1, 2000 and August 26, 2008 within the National Registry of Cardiopulmonary Resuscitation. Survival outcomes of patients requiring hemodynamic support immediately before CPA were compared with those of patients who did not receive hemodynamic support (pressors), using multivariable logistic regression analyses to adjust for differences in demographics and clinical characteristics. Pressor medications included epinephrine, norepinephrine, phenylephrine, dopamine, dobutamine, and vasopressin. MEASUREMENTS AND MAIN RESULTS: The overall rate of survival to hospital discharge was 15.9%. Patients taking pressors before CPA were less likely to survive to discharge (9.3 vs. 21.2%; P < 0.0001). After multivariable adjustment, patients taking pressors before pulseless CPA were 55% less likely to survive to discharge (adjusted odds ratio [OR], 0.45; 95% confidence interval [CI], 0.42-0.48). Age equal to or greater than 65 years (adjusted OR, 0.77; 95% CI, 0.73-0.82), nonwhite race (adjusted OR, 0.58; 95% CI, 0.54-0.62), and mechanical ventilation (adjusted OR, 0.60; 95% CI, 0.56-0.63) were also variables that could be identified before CPA that were independently associated with lower survival. More than half of survivors were discharged to rehabilitation or extended care facilities. Only 3.9% of patients who had CPA despite pressors were discharged home from the hospital, as compared with 8.5% of patients with a CPA and not taking pressors (adjusted OR, 0.53; 95% CI, 0.49-0.59). CONCLUSIONS: Although overall survival of ICU patients was 15.9%, patients requiring pressors and who experienced a CPA in an ICU were half as likely to survive to discharge and to be discharged home than patients not taking pressors. This study provides robust estimates of CPR outcomes of critically ill patients, and may assist clinicians to inform consent for this procedure.
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Reanimación Cardiopulmonar/métodos , Enfermedad Crítica/epidemiología , Enfermedad Crítica/terapia , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Reanimación Cardiopulmonar/estadística & datos numéricos , Estudios de Cohortes , Femenino , Paro Cardíaco/epidemiología , Paro Cardíaco/terapia , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Análisis de Supervivencia , Estados Unidos/epidemiología , Vasoconstrictores/administración & dosificación , Adulto JovenRESUMEN
PURPOSE OF REVIEW: To summarize the literature to date on endoscopic mucosal removal techniques as applied to the upper gastrointestinal tract, predominantly the stomach and esophagus. This is an area that has rapidly advanced in terms of new procedures and techniques with a large body of outcomes that support their use. RECENT FINDINGS: The resection techniques can be divided into two forms, mucosal resection and submucosal dissection. Mucosal resection is typically done with cap techniques and is more suitable for removable of neoplastic lesions that are less than 1.5 cm in size. Submucosal dissection techniques are more difficult, associated with increased complications, and typically reserved for lesions greater than 1.5 cm and less than 3 cm in size. Ideal lesions for mucosal resection are generally flat and are located in areas easily accessible by the endoscope. SUMMARY: Endoscopic tissue removal methods are capable of removing neoplastic lesions en bloc in the upper gastrointestinal tract. These techniques fulfill cancer treatment guidelines by having histological confirmation of total removal of neoplastic lesions with assessment of the margins of resections. Long-term clinical outcomes of these techniques are emerging and seem promising in terms of disease-free and overall survival.
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Endoscopía Gastrointestinal/métodos , Neoplasias Esofágicas/cirugía , Mucosa Intestinal/cirugía , Neoplasias Gástricas/cirugía , Neoplasias Esofágicas/patología , Humanos , Mucosa Intestinal/patología , Estadificación de Neoplasias , Neoplasias Gástricas/patología , Resultado del TratamientoRESUMEN
OBJECTIVES: Colonoscopy surveillance interval data longer than 5 years are limited. We examined adenoma yield to identify factors that predict appropriate intervals for postpolypectomy surveillance greater than 5 years, including risk of advanced adenoma recurrence. METHODS: We identified patients with and without adenomas on an index colonoscopy who returned at 5 to 10 years for a follow-up colonoscopy. Multivariate logistic regression was used to identify variables that predict finding an adenoma on follow-up colonoscopy. RESULTS: Three hundred ninety-nine patients were identified with a follow-up colonoscopy at an interval of >5 years. Irrespective of surveillance interval, adenoma incidence occurred in 116 patients (29.1%) with 25 (6%) having advanced adenomas. Patients with nonadvanced adenomas on index colonoscopy had a similar risk of advanced adenoma on follow-up colonoscopy at 5 years versus 6 to 10 years, 5% versus 6.2% (P=0.39). The risk of advanced adenoma at 5 and 6 to 10 years in patients with a negative index colonoscopy was 7% versus 3.6% (P=0.15). Patients with an advanced adenoma at index colonoscopy had the highest rate of advanced adenoma detection at 5 years at 26%. Proximal polyp location (odds ratio 12.4, confidence interval 2.7-56.7) predicted advanced adenoma occurrence at 5 years. CONCLUSIONS: Postpolypectomy colonoscopy intervals can be extended beyond 5 years in patients with nonadvanced adenomas. Our findings also support a rescreening interval of 5 to 10 years in patients with a negative index colonoscopy. Patients with an index advanced adenoma are at highest risk for recurrent advanced adenoma and should have repeat colonoscopy before a 5 years interval.
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Adenoma/prevención & control , Pólipos del Colon/cirugía , Colonoscopía/métodos , Neoplasias Colorrectales/prevención & control , Adenoma/diagnóstico , Pólipos Adenomatosos/cirugía , Anciano , Neoplasias Colorrectales/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Acute kidney injury (AKI), defined as an increment in serum creatinine level of 0.3 mg/dL or greater in 48 hours, is associated with poor outcomes. The prognosis associated with an increased creatinine level, either on admission or that develops in the hospital (ie, AKI), that rapidly returns to normal is not known. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 6,033 patients admitted to medical wards of a community teaching hospital between 2005 and 2007. PREDICTOR: AKI was defined as an increase in serum creatinine level of 0.3 mg/dL or greater within 48 hours. Increased serum creatinine level on admission was defined as serum creatinine greater than1.2 mg/dL on hospital admission in patients who did not subsequently meet criteria for AKI. Patients with a serum creatinine level of 1.2 mg/dL or less who had no increase of 0.3 mg/dL or greater within 48 hours during their hospital stay served as controls. OUTCOMES & MEASUREMENTS: Mortality, length of stay, intensive care unit transfer, and discharge destination were outcomes of interest. RESULTS: Of 6,033 patients, 735 had AKI. Of these, 443 (60%) had serum creatinine levels that subsequently decreased by 0.3 mg/dL or greater within 48 hours and 197 returned to normal levels within 48 hours. Overall, patients with AKI had significantly greater mortality rates (14.8%) than patients without AKI with increased serum creatinine levels on admission (2.5%) and controls (1.3%; P < 0.001). Patients with AKI with a serum creatinine level that returned to normal within 48 hours had substantially greater mortality rates (14.2%) than those who initially presented with an increased serum creatinine level on admission and subsequent serum creatinine level decrease of 0.3 mg/dL or greater to normal within 48 hours (2.5%; P < 0.01). LIMITATIONS: Sample sizes of subgroups were small. Causes of AKI and increases in serum creatinine levels on admission were not assessed. CONCLUSIONS: An increase in serum creatinine level of 0.3 mg/dL or greater during 48 hours of hospitalization predicts outcomes even if the value returns to normal. Patients who present to the hospital with an increased creatinine level that returns rapidly to normal have outcomes approaching those with serum creatinine levels consistently in the normal range.
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Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/terapia , Hospitales Universitarios/tendencias , Lesión Renal Aguda/sangre , Anciano , Estudios de Cohortes , Creatinina/sangre , Femenino , Hospitalización/estadística & datos numéricos , Hospitalización/tendencias , Hospitales Universitarios/estadística & datos numéricos , Humanos , Unidades de Cuidados Intensivos/tendencias , Tiempo de Internación/tendencias , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Acute pancreatitis is a painful inflammatory disorder known to occur in children. Recent reports, primarily on the basis of adult data, have suggested an increasing incidence. However, pediatric studies are limited. OBJECTIVE: The study was performed to examine the frequency of acute pancreatitis in a pediatric population from 1994 to 2007 and to characterize etiologies by age subsets. PATIENTS AND METHODS: In this retrospective study, cases of pancreatitis were identified by ICD-9 codes and subjected to inclusion criteria. RESULTS: Two hundred and seventy-one cases of pancreatitis met inclusion criteria. Mean age of the subjects was 13.1 +/- 5.6 years. The recurrence rate was 15.3%. Biliary disease was the most common etiology (32.6%). Acute pancreatitis cases evaluated at a single tertiary care center increased 53% between 1995 to 2000 and 2001 to 2006 (P < 0.02). However, when cases were normalized by all annual pediatric emergency department visits for all medical reasons, the increase was reduced to 22% and lost statistical significance (P = 0.16). The rise was not associated with a change in etiologies or body mass index (BMI). CONCLUSIONS: This is the first report demonstrating that an increase in pediatric pancreatitis may in part be due to growing referrals to tertiary care centers. The data on etiologies, particularly with regard to differing ages, may be helpful in managing children who present with acute pancreatitis.
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Enfermedades de las Vías Biliares/complicaciones , Pancreatitis/epidemiología , Derivación y Consulta/tendencias , Adolescente , Niño , Femenino , Humanos , Incidencia , Masculino , Pancreatitis/etiología , Recurrencia , Estudios Retrospectivos , Distribución por SexoRESUMEN
This paper has been retracted.