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OBJECTIVES: The COVID-19 outbreak severely affected long-term care (LTC) service provision. This study aimed to quantitatively evaluate its impact on the utilization of LTC services by older home-dwelling adults and identify its associated factors. DESIGN: A retrospective repeated cross-sectional study. SETTING AND PARTICIPANTS: Data from a nationwide LTC Insurance Comprehensive Database comprising monthly claims from January 2019 to September 2020. METHODS: Interrupted time series analyses and segmented negative binomial regression were employed to examine changes in use for each of the 15 LTC services. Results of the analyses were synthesized using random effects meta-analysis in 3 service types (home visit, commuting, and short-stay services). RESULTS: LTC service use declined in April 2020 when the state of emergency (SOE) was declared, followed by a gradual recovery in June after the SOE was lifted. There was a significant association between decline in LTC service use and SOE, whereas the association between LTC service use and the status of the infection spread was limited. Service type was associated with changes in service utilization, with a more precipitous decline in commuting and short-stay services than in home visiting services during the SOE. Service use by those with dementia was higher than that by those without dementia, particularly in commuting and short-stay services, partially canceling out the decline in service use that occurred during the SOE. CONCLUSIONS AND IMPLICATIONS: There was a significant decline in LTC service utilization during the SOE. The decline varied depending on service types and the dementia severity of service users. These findings would help LTC professionals identify vulnerable groups and guide future plans geared toward effective infection prevention while alleviating unfavorable impacts by infection prevention measures. Future studies are required to examine the effects of the LTC service decline on older adults.
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COVID-19 , Demência , Humanos , Idoso , Assistência de Longa Duração , Estudos Retrospectivos , Japão/epidemiologia , Estudos Transversais , COVID-19/complicações , Demência/complicaçõesRESUMO
Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel liver fibrosis biomarker, but there are few studies on M2BPGi in liver transplantation (LT) recipients. This study aimed to evaluate the utility of M2BPGi measurement in LT recipients. We collected the clinicopathological data of 233 patients who underwent a liver biopsy at Kyoto University Hospital after LT between August 2015 and June 2019. The median values of M2BPGi in patients with METAVIR fibrosis stages F0, F1, F2, and ≥F3 were 0.61, 0.76, 1.16, and 1.47, respectively, whereas those in patients with METAVIR necroinflammatory indexes A0, A1, and ≥A2 were 0.53, 1.145, and 2.24, respectively. Spearman rank correlation test suggested that the necroinflammatory index had a stronger correlation to the M2BPGi value than the fibrosis stage. The area under the receiver operating characteristic curve of M2BPGi to predict ≥A1 was 0.75, which was significantly higher than that of any other liver fibrosis and inflammation marker. Patients with a rejection activity index (RAI) of ≥3 had a higher M2BPGi value than those with RAI ≤ 2 (P = 0.001). Patients with hepatitis C virus viremia had a higher M2BPGi value than sustained virological responders or those with other etiologies. In conclusion, the present study demonstrated that M2BPGi values are more strongly influenced by necroinflammatory activity and revealed M2BPGi, which has been thought to be a so-called fibrosis marker, as a disease activity marker in transplant recipients. M2BPGi measurement may be useful to detect early stage liver inflammation that cannot be detected by routine blood examination of LT recipients.
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Transplante de Fígado , Glicosilação , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/cirurgia , Transplante de Fígado/efeitos adversos , Glicoproteínas de Membrana/metabolismo , Curva ROCRESUMO
BACKGROUND: The indocyanine green test is used widely to evaluate the risk of posthepatectomy liver failure for hepatocellular carcinoma. A more convenient and reliable scoring system is desired owing to limited accuracy and availability of the indocyanine green test. This study aimed to establish a new selection criterion for liver resection in HCC. METHODS: We reviewed retrospectively 876 patients undergoing a partial hepatectomy for hepatocellular carcinoma between 2007 and 2015 in 8 affiliated hospitals. Posthepatectomy liver failure grades B and C were regarded as posthepatectomy liver failure. We identified the risk factors for posthepatectomy liver failure and established a predictive model based on a formula for the probability of posthepatectomy liver failure. External validation was performed in an additional cohort of 250 patients. RESULTS: Posthepatectomy liver failure occurred in 92 patients (11%). The area under the receiver operating characteristic curve for the prediction of posthepatectomy liver failure was 0.646 for the platelet count, 0.641 for albumin, 0.623 for the percentage of liver remnant, and 0.607 for the plasma disappearance rate of indocyanine green. Logistic regression analysis provided a formula for the probability of posthepatectomy liver failure consisting of platelet count, albumin, and liver remnant. We defined platelet count + 90 × albumin as the ALPlat index and established an ALPlat-based criterion for operative resection that secured the same risk assumed by the indocyanine green-based criterion (Makuuchi's criterion). This criterion exhibited a greater sensitivity and specificity than the indocyanine green-based criterion in the validation cohort. CONCLUSION: The ALPlat criterion is a simple and useful method to assess liver function and to make therapeutic decisions in patients with hepatocellular carcinoma.
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Hepatectomia/efeitos adversos , Falência Hepática/etiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de RiscoRESUMO
AIM: Liver biopsy is the gold standard for assessing liver fibrosis (LF) after liver transplantation (LT), but its invasiveness limits its utility. This study aimed to evaluate the usefulness of liver stiffness measurement (LSM) using acoustic radiation force impulse (ARFI) imaging to assess LF after LT. METHODS: Between September 2013 and January 2017, 278 patients who underwent liver biopsy after LT in Kyoto University Hospital (Kyoto, Japan) were prospectively enrolled. Liver stiffness measurement was carried out using ARFI imaging; its value was expressed as shear wave velocity (Vs) [m/s]. The LF was evaluated according to METAVIR score (F0-F4). The diagnostic performance of Vs for F2≤ and F3≤ was assessed and compared with that of laboratory tests using receiver operating characteristic (ROC) analysis. RESULTS: The median Vs values increased according to the progression of LF (F0, 1.18 (0.78-1.92); F1, 1.35 (0.72-3.54); F2, 1.55 (1.05-3.37); F3, 1.84 (1.41-2.97)). The Vs had the highest area under the ROC curve (AUROC) for the prediction of both F2 ≤ and F3 ≤ fibrosis (F2, 0.77; and F3, 0.85). With the cut-off value of Vs >1.31, sensitivity, specificity, positive predictive value, and negative predictive value were 89.4%, 53.3%, 37.3%, and 94.2% in predicting F2≤, respectively. Shear wave velocity diagnosed LF better than any laboratory tests regardless of the type of primary disease. CONCLUSIONS: Acoustic radiation force impulse helps to assess graft LF after LT. The high sensitivity suggested that ARFI might reduce the frequency of liver biopsies by detecting patients who are unlikely to have significant fibrosis after LT. (Unique trial no. UMIN R000028296.).
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OBJECTIVES: The origin of collagen-producing myofibroblasts in pancreatic fibrosis is still controversial. Pancreatic stellate cells (PSCs), which have been recognized as the pancreatic counterparts of hepatic stellate cells (HSCs), are thought to play an important role in the development of pancreatic fibrosis. However, sources of myofibroblasts other than PSCs may exist because extensive studies of liver fibrosis have uncovered myofibroblasts that did not originate from HSCs. This study aimed to characterize myofibroblasts in an experimental pancreatic fibrosis model in mice. METHODS: We used transgenic mice expressing green fluorescent protein via the collagen type I α1 promoter and induced pancreatic fibrosis with repetitive injections of cerulein. RESULTS: Collagen-producing cells that are negative for glial fibrillary acidic protein (ie, not derived from PSCs) exist in the pancreas. Pancreatic stellate cells had different characteristics from those of HSCs in a very small possession of vitamin A using mass spectrometry and a low expression of lecithin retinol acyltransferase. The microstructure of PSCs was entirely different from that of HSCs using flow cytometry and electron microscopy. CONCLUSIONS: Our study showed that characteristics of PSCs are different from those of HSCs, and myofibroblasts in the pancreas might be derived not only from PSCs but also from other fibrogenic cells.
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Colágeno/biossíntese , Células Estreladas do Fígado/metabolismo , Pâncreas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Animais , Células Cultivadas , Colágeno/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/ultraestrutura , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica , Microscopia de Fluorescência , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Miofibroblastos/ultraestrutura , Pâncreas/citologia , Células Estreladas do Pâncreas/citologia , Células Estreladas do Pâncreas/ultraestruturaRESUMO
BACKGROUND: Nonalcoholic fatty liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Kupffer cells play a central role in promoting hepatic inflammation, which leads to the development of NASH. We investigated the anti-inflammatory effect of hepatic vagus-mediated stimulation of the α7 nicotinic acetylcholine receptor (α7nAChR) on Kupffer cells in NASH pathogenesis. METHODS: Wild-type (WT) mice undergoing hepatic vagotomy (HV) were fed a methionine- and choline-deficient (MCD) diet for 1 week. α7nAChR knockout (α7KO) chimeric mice were generated by transplanting α7KO bone marrow cells into irradiated and Kupffer cell-deleted WT recipients. Kupffer cells were isolated from WT mice and treated with α7nAChR agonist under stimulation by lipopolysaccharide and/or palmitic acid. RESULTS: HV aggravated MCD diet-induced NASH in both steatosis and inflammation. The hepatic inflammatory response, including the upregulation of tumor necrosis factor alpha (TNFα), interleukin (IL)-12, and monocyte chemoattractant protein 1 (MCP-1), was accelerated in HV mice, accompanied by the downregulation of PPARα pathway genes. Kupffer cells were highly activated via the phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-κB) in MCD diet-fed HV mice. The α7nAchR agonist suppressed the inflammatory response of primary Kupffer cells induced by lipopolysaccharide and palmitic acid by attenuating the NF-κB cascade. α7KO chimeric mice fed an MCD diet for 1 week developed advanced NASH with highly activated Kupffer cells. The hepatic expression of TNFα, IL-12, and MCP-1 was upregulated in α7KO chimeric mice, accompanied by abnormal lipid metabolism. CONCLUSIONS: Hepatic vagus activity regulates the inflammatory response of Kupffer cells via α7nAChR in NASH development.
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Células de Kupffer/metabolismo , Fígado/inervação , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Nervo Vago/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Quimiocina CCL2/genética , Quimera , Colina/administração & dosagem , Deficiência de Colina/metabolismo , Regulação para Baixo , Subunidade p35 da Interleucina-12/genética , Lipopolissacarídeos/farmacologia , Masculino , Metionina/administração & dosagem , Metionina/deficiência , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , PPAR alfa/genética , Ácido Palmítico/farmacologia , Fosforilação , Fator de Necrose Tumoral alfa/genética , Regulação para Cima , Vagotomia , Estimulação do Nervo Vago , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/deficiência , Receptor Nicotínico de Acetilcolina alfa7/genéticaRESUMO
OBJECTIVE: The aim of this study was to evaluate the usefulness of the Mac-2 binding protein glycosylation isomer (M2BPGi) for the prediction of posthepatectomy liver failure (PHLF) in hepatocellular carcinoma (HCC) patients. SUMMARY BACKGROUND DATA: M2BPGi is a novel serum marker of liver fibrosis. The usefulness of M2BPGi for the prediction of PHLF has not been evaluated. METHODS: Clinicopathological data were analyzed in 138 HCC patients who underwent liver resection between August 2011 and November 2014. PHLF was evaluated according to the definition of the International Study Group of Liver Surgery. Performance of preoperative parameters in predicting PHLF was determined using receiver operating characteristic (ROC) analysis. RESULTS: Serum M2BPGi level correlated with the METAVIR fibrosis score. M2BPGi levels of hepatitis C virus (HCV)-positive patients were significantly higher than those of HCV-negative patients, even in the same fibrosis stage. PHLF ≥ Grade B developed in 19 patients (13.8%). The area under the ROC curve (AUROC) of M2BPGi for the prediction of PHLF ≥ Grade B was 0.71. In multivariate analysis, M2BPGi [odds ratio (OR): 2.08, 95% confidence interval (CI) 1.28-3.55], platelet count (OR: 0.39, 95% CI 0.18-0.80), and resection rate (OR: 2.71, 95% CI 1.46-5.40) were the significant factors associated with PHLF ≥ Grade B. The AUROC of the PHLF index defined by these factors was 0.81. Notably, in patients with HCV infection, the predictive ability of M2BPGi for PHLF (AUROC 0.85) was the best among the preoperative parameters. CONCLUSIONS: M2BPGi is a useful predictor of PHLF, especially in patients with HCV infection.
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Antígenos de Neoplasias/sangue , Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Falência Hepática/diagnóstico , Neoplasias Hepáticas/cirurgia , Glicoproteínas de Membrana/sangue , Complicações Pós-Operatórias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Combinação de Medicamentos , Feminino , Glicosilação , Humanos , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Psyllium , Estudos Retrospectivos , Extrato de SennaRESUMO
BACKGROUND: The incidence of iatrogenic pseudoaneurysms has recently increased due to the more frequent use of high doses of anticoagulants in apheresis therapy. The reason why the decision for an appropriate dose of the anticoagulant is difficult is that such information about the material properties of adsorbers is not provided. OBJECTIVE: To investigate the calculations to determine the optimal dose of heparin sodium to administer during apheresis. METHODS: The calculations were based on experimental data obtained during an in vivo test using dogs and theoretical pharmacokinetics data obtained using a one compartment model. RESULTS: When information regarding the adsorption isotherm of the adsorbent material that takes competitive adsorption into consideration was provided, the required anticoagulant dose for apheresis could be determined. CONCLUSIONS: It is important to decide the optimal dose of anticoagulant that Information about the material's characteristics including data about its adsorption isotherm that takes competitive adsorption into consideration are provided before therapy. Then, if so, the calculation for required dose must be possible.
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Anticoagulantes/administração & dosagem , Remoção de Componentes Sanguíneos , Heparina/administração & dosagem , Adsorção , Animais , Anticoagulantes/sangue , Anticoagulantes/uso terapêutico , Remoção de Componentes Sanguíneos/instrumentação , Remoção de Componentes Sanguíneos/métodos , Cães , Cálculos da Dosagem de Medicamento , Desenho de Equipamento , Heparina/sangue , Heparina/uso terapêuticoRESUMO
BACKGROUND: Posthepatectomy liver failure (PHLF) is a potentially fatal complication, and the accurate prediction of PHLF is essential. Liver stiffness measurement (LSM) has been accepted widely as a noninvasive assessment for liver fibrosis. We aimed to evaluate the usefulness of LSM in predicting PHLF. METHODS: One hundred seventy-seven patients with hepatocellular carcinoma who underwent liver resection between August 2011 and October 2014 were analyzed prospectively. LSM was performed by Virtual Touch Tissue Quantification based on acoustic radiation force impulse imaging, and its value was expressed as the shear wave velocity (Vs) [m/s]. The remnant liver volume rate (Rem) was calculated by computed tomography volumetry. PHLF was diagnosed on the basis of the definition from the International Study Group of Liver Surgery. RESULTS: PHLF occurred in 38 patients (21.5%): grade A, 17 patients (9.6%); grade B, 15 patients (8.5%); and grade C, 6 patients (3.4%). The area under the receiver operating characteristic curve of the Vs for predicting PHLF was 0.67 for grade ≥A, 0.78 for grade ≥B, and 0.74 for grade C, which was greater than any other preoperative factor for each grade. Multivariate stepwise selection identified 2 significant factors associated with PHLF grade ≥B: Vs (odds ratio, 2.66; 95% confidence interval, 1.69-4.41, P < .01) and Rem (odds ratio, 0.47; 95% confidence interval, 0.27-0.79, P < .01). The logistic model that included the Vs and Rem resulted in an area under the receiver operating characteristic curve of 0.80 for predicting PHLF grade ≥B. CONCLUSION: LSM was useful for the prediction of PHLF and the estimation of the safe Rem range.
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Carcinoma Hepatocelular/cirurgia , Hepatectomia , Cirrose Hepática/diagnóstico , Falência Hepática/diagnóstico , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/diagnóstico , Adulto , Idoso , Feminino , Humanos , Cirrose Hepática/complicações , Falência Hepática/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Curva ROC , Medição de RiscoRESUMO
BACKGROUND: Sustained liver injury causes liver fibrosis and eventually cirrhosis. Understanding the pathophysiological mechanisms of liver fibrosis and interventions in the fibrotic process is crucial for improving the prognosis of patients with chronic liver diseases. Although studies have shown that splenectomy suppresses liver fibrosis, the mechanism by which this occurs is poorly understood. The present study focuses on the immunological functions of the spleen to investigate its role in liver fibrosis. METHODS: BALB/c and severe combined immunodeficiency (SCID) mice underwent splenectomies or sham operations prior to induction of liver fibrosis with carbon tetrachloride or thioacetamide. RESULTS: Sirius red staining and hydroxyproline assays showed that splenectomy suppressed liver fibrogenesis in BALB/c mice. Reverse transcription PCR analysis of T helper type 1 (Th1) and T helper type 2 (Th2) cytokines demonstrated that splenectomy shifted the Th1/Th2 balance in the liver towards Th1 dominance. In SCID mice, the inhibitory effect on liver fibrosis was abrogated. The number of CD4(+) T helper lymphocytes in the spleen decreased after liver injury. Green fluorescent protein positive (GFP(+)) splenocytes were transplanted into the spleens of syngeneic wild-type mice to trace their destination after fibrosis induction. GFP(+)CD4(+) lymphocytes appeared in the liver after induction of fibrosis, and flow cytometry revealed the vast majority of them were Th2 lymphocytes. Transfer of splenocytes via the portal vein into syngeneic splenectomized mice cancelled the suppressive effect of splenectomy on liver fibrosis. CONCLUSIONS: The present study demonstrated that Th2-dominant splenic lymphocytes migrate into the liver and promote liver fibrosis by shifting the cytokine balance towards Th2 dominance. Splenectomy suppresses the progression of fibrosis at least partly by restoring the Th1/Th2 balance.
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Citocinas/sangue , Cirrose Hepática/patologia , Baço/patologia , Linfócitos T Auxiliares-Indutores/patologia , Animais , Movimento Celular , Modelos Animais de Doenças , Progressão da Doença , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Excessive acetaminophen (APAP) use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK)-dependent necrosis (or necroptosis), which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia-reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.
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OBJECTIVE: Although [(18)F]-FDG is a useful oncologic PET tracer, FDG uptake is known to be low in a certain type of hepatocellular carcinoma (HCC). [(18)F]-fluoroacetate ((18)F-FACE) is an [(18)F] fluorinated acetate, which is known to be converted into fatty acids, incorporated in membrane and is expected to be a promising oncologic PET tracer. The aim of this study was to evaluate the usefulness of (18)F-FACE as an oncologic PET tracer in preclinical study in healthy volunteers and in patients with liver tumors. METHODS: Twenty-four healthy volunteers (age 48.2 ± 12.9 years old; 15 male and 9 female) and ten patients with liver tumor (age 72.1 ± 7.0 years old; 6 male and 4 female) were included. We performed whole-body static PET/CT scan using (18)F-FACE (n = 34) and (18)F-FDG (n = 5 for volunteers, n = 8 for patients) on each day, respectively. Qualitative analysis and quantitative analysis of tumors (5 HCCs, 1 cholangiocellular carcinoma, 4 metastatic tumors from colon cancer and P-NET) were performed using SUVmax and tumor-to-normal liver ratio (TNR). RESULTS: In healthy volunteers, (18)F-FACE was metabolically stable in vivo and its biodistribution was almost similar to blood pool, basically uniformly independent of age and gender during PET scan time (up to 3 h). Normal physiological uptake of (18)F-FACE at each organ including liver (SUVmean 1.8 ± 0.2) was lower than that of blood pool (SUVmean 2.3 ± 0.3) at 1 h after injection. Chronic inflammatory uptake around femur of post-operative state of femoral osteotomy and faint uptake of benign hemangioma were observed in a case of healthy volunteer. (18)F-FACE (SUVmax 2.7 ± 0.6, TNR 1.5 ± 0.4) of liver tumors was significantly lower than those of (18)F-FDG uptake (6.5 ± 4.2, 2.6 ± 1.7, respectively). In qualitative analysis, (18)F-FDG was positive in 4 tumors (3 HCCs, 1 CCC) and negative in the other 6 tumors, while (18)F-FACE was also positive in 4 tumors which were the same tumors with positive (18)F-FDG uptake. CONCLUSIONS: Biodistribution of (18)F-FACE was appropriate for oncologic imaging. Tumor (18)F-FACE uptake was positive in four patients with HCC and CCC, but the uptake pattern was similar to (18)F-FDG. Further evaluation was needed.
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Fluoracetatos , Neoplasias Hepáticas/diagnóstico por imagem , Compostos Radiofarmacêuticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/diagnóstico por imagem , Colangiocarcinoma/diagnóstico por imagem , Neoplasias do Colo/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual , Tomografia Computadorizada por Raios X/métodos , Imagem Corporal Total/métodosRESUMO
AIM: Liver fibrosis is the universal consequence of chronic liver diseases. Sustained hepatocyte injury initiates an inflammatory response, thereby activating hepatic stellate cells, the principal fibrogenic cells in the liver. Reactive oxygen species are involved in liver injury and are a promising target for treating liver fibrosis. Hydrogen water is reported to have potential as a therapeutic tool for reactive oxygen species-associated disorders. This study aimed to investigate the effects of hydrogen water on liver fibrogenesis and the mechanisms underlying these effects. METHODS: C57BL/6 mice were fed with hydrogen water or control water, and subjected to carbon tetrachloride, thioacetamide and bile duct ligation treatments to induce liver fibrosis. Hepatocytes and hepatic stellate cells were isolated from mice and cultured with or without hydrogen to test the effects of hydrogen on reactive oxygen species-induced hepatocyte injuries or hepatic stellate cell activation. RESULTS: Oral intake of hydrogen water significantly suppressed liver fibrogenesis in the carbon tetrachloride and thioacetamide models, but these effects were not seen in the bile duct ligation model. Treatment of isolated hepatocyte with 1 µg/mL antimycin A generated hydroxyl radicals. Culturing in the hydrogen-rich medium selectively suppressed the generation of hydroxyl radicals in hepatocytes and significantly suppressed hepatocyte death induced by antimycin A; however, it did not suppress hepatic stellate cell activation. CONCLUSION: We conclude that hydrogen water protects hepatocytes from injury by scavenging hydroxyl radicals and thereby suppresses liver fibrogenesis in mice.
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BACKGROUND AND AIMS: Hepatic steatosis is a metabolic liver disease with the potential to progress to steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The aim of this study was to investigate the impact of CCAAT/enhancer-binding protein homologous protein (CHOP) deficiency in the development of steatosis-associated progression of HCC. METHODS: Eight-week-old wild-type (WT) and CHOP knockout (CHOP-/-) mice were fed a normal or methionine-choline-deficient (MCD) diet. Mice were sacrificed after 3 weeks, and steatosis, inflammation, apoptosis, and liver damage were assessed. We also evaluated fibrosis after 8 weeks of nutrition intervention. To explore the role of CHOP in liver carcinogenesis, 25 mg/kg of diethylnitrosamine (DEN) was injected intraperitoneally into 2-week-old mice, which were then fed the aforementioned diets from 8 to 24 weeks of age. CHOP expression in HCC patient livers was also evaluated. RESULTS: CHOP deficiency did not affect steatosis but significantly reduced apoptotic cells, inflammation scores, and serum liver enzymes. It also significantly suppressed total serum bilirubin levels, fibrotic area size, and messenger RNA expression of profibrotic cytokines. DEN-initiated carcinogenesis was promoted by the MCD diet, while CHOP deficiency significantly attenuated the total number and maximum diameter of tumors and the Ki-67 labeling index. In human livers, CHOP expression was enhanced in parallel with non-alcoholic steatohepatitis-to-HCC progression. CONCLUSIONS: CHOP deficiency attenuated apoptosis, inflammation, fibrosis, and tumorigenesis under fat-loading conditions, indicating that a therapeutic strategy targeting CHOP might be effective for fat-induced liver injury and protecting against promotion of carcinogenesis in patients with liver steatosis.
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Proteínas Estimuladoras de Ligação a CCAAT/deficiência , Carcinoma Hepatocelular/terapia , Deficiência de Colina , Fígado Gorduroso/terapia , Cirrose Hepática/terapia , Neoplasias Hepáticas/terapia , Metionina/deficiência , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/etiologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Feminino , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Terapia de Alvo MolecularRESUMO
We report a case of multiple lung metastases from hepatocellular carcinoma(HCC)successfully treated by oral administration of tegafur/uracil(UFT). A 70-year-old man underwent left hepatic lobectomy for HCC. Intrahepatic recurrence appeared 3 months after the operation and multiple lung metastases appeared at 6 months. Transarterial chemoembolization and radiofrequency ablation were applied for intrahepatic recurrences, and oral administration of UFT(300 mg/day)was initiated for lung metastases. Four months after the initiation of UFT therapy, CT scan showed complete remission(CR)of liver and lung lesions, and elevated AFP and PIVKA-II levels returned to normal. Although the patient underwent a partial hepatectomy for solitary intrahepatic recurrence 2 years later, CR of lung metastases was maintained. The present case suggests the clinical usefulness of UFT for HCC with extrahepatic recurrences, given that effective systemic treatments for HCC are currently limited.
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Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Administração Oral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/secundário , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Masculino , Indução de Remissão , Tegafur/administração & dosagem , Uracila/administração & dosagemRESUMO
BACKGROUND: Donor safety is a major concern in living-donor liver transplantation. However, partial grafts do not meet the functional demands of recipients and lead to small-for-size syndrome (SFSS). In a previous study, we showed that olprinone (OLP), a selective phosphodiesterase ÐÐÐ inhibitor, up-regulates endothelial nitric oxide synthase level in the liver and attenuates shear stress, sinusoidal endothelial cell injury, and hepatocyte apoptosis after excessive liver resection in a rat model. We aimed to examine whether OLP treatment has beneficial effects on SFSS in a rat model of partial liver transplantation (PLT). METHODS: We performed experiments in a rat model of 30% PLT. In the OLP group, we inserted an osmotic pump with OLP into the peritoneal cavity 48 h before liver graft sampling. Recipient rats were not treated with OLP. We examined the liver microstructure by electron microscopy and biochemical examination, and determined the 7-d survival of recipients. RESULTS: In the OLP group 1 h after PLT, the sinusoidal endothelial cells of the liver were well preserved and we observed few vacuolar structures in hepatocytes. The total serum bilirubin level 1 wk after PLT tended to be lower in the OLP group than in the controls, and the liver microstructures were also well preserved in the OLP group. The probability of survival in the OLP group (100%; 14 of 14 rats) was significantly higher than that in the control group (75%; 15 of 20 rats). CONCLUSIONS: Olprinone treatment was demonstrated to have therapeutic potential to overcome SFSS.
Assuntos
Imidazóis/uso terapêutico , Falência Hepática/prevenção & controle , Transplante de Fígado/efeitos adversos , Fígado/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/uso terapêutico , Piridonas/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Imidazóis/farmacologia , Fígado/ultraestrutura , Masculino , Tamanho do Órgão , Inibidores da Fosfodiesterase 3/farmacologia , Piridonas/farmacologia , Ratos , Ratos Endogâmicos LewRESUMO
During the course of studying selenocysteine (Sec) synthesis mechanisms in mammals, we prepared selenophosphate synthetase (SPS) from bovine liver by 4-step chromatography. In the last step of chromatography of hydroxyapatite, we found a protein band of molecular mass 33 kDa on SDS-PAGE, consistent with the pattern of SPS activity that was indirectly manifested by [(75)Se]Sec production activity; however, we could not detect significant Se content in this active fraction. We also found a clear band of 33 kDa by Western blotting with antibody against a common peptide (387-401) in SPS2. We detected selenophosphate as the product of this active enzyme in the reaction mixture, composed of ATP, [(75)Se]H(2)Se and SPS. Chemically synthesized selenophosphate plays a role in Sec synthesis, not the addition of this enzyme. These results support that the product of SPS2 is selenophosphate itself. During this investigation, the probable sequence of bovine SPS2 not having Sec was reported in the blast information and the molecular mass was near with the protein in this report. Thus, bovine active SPS2 of molecular mass 33 kDa does not contain Sec.