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Background Patients undergoing hemodialysis are susceptible to sarcopenia. As intracellular reservoirs of water, skeletal muscles are important contributors to intradialytic hypotension. This study was designed to determine the role of skeletal muscle mass in intradialytic hypotension. Methods In a cross-sectional study, the body composition of 177 patients was measured immediately after hemodialysis using bioelectrical impedance analysis. The parameters measured were skeletal muscle mass, intracellular and extracellular water contents, total body water, and cell-membrane functionality (in phase angle at 50 kHz). Data from laboratory tests, chest radiography, measurements of handgrip strength and mid-arm circumference, and questionnaires were collected. The main outcome was intradialytic hypotension, defined as more than two episodes of hypotension (systolic blood pressure of

Background Mac-2 binding protein glycosylation isomer (M2BPGi) was introduced as a noninvasively measurable serologic marker for liver fibrosis. Acoustic radiation force impulse imaging (ARFI) elastography is another noninvasive method of measuring hepatic fibrosis. There are limited data about the correlations between histologic fibrosis grade and noninvasively measured markers, including M2BPGi and ARFI. Methods This prospective study was conducted among patients admitted consecutively for liver resection, cholecystectomy, or liver biopsy. ARFI elastography, serum M2BPGi levels, and the aspartate aminotransferase to platelet ratio index (APRI) score were evaluated before histologic evaluation. Histologic interpretation was performed by a single pathologist using the METAVIR scoring system. Results In patients with high METAVIR scores, M2BPGi levels and ARFI values showed statistically significant differences between patients with fibrosis and those without fibrosis. In 41 patients with hepatocellular carcinoma, as METAVIR scores increased, M2BPGi levels also tended to increase (p=0.161). ARFI values changed significantly as METAVIR scores increased (p=0.039). In 33 patients without hepatocellular carcinoma, as METAVIR scores increased, M2BPGi levels significantly increased (p=0.040). ARFI values also changed significantly as METAVIR scores increased (p=0.033). M2BPGi levels were significantly correlated with ARFI values (r=0.604, p

Alcohol-related liver disease (ALD) has become the major cause of liver transplantation (LT) in Korea, and is currently the most common cause of LT in Europe and the United States. Although, ALD is one of the most common indications for LT, it is traditionally not considered as an option for patients with ALD due to organ shortages and concerns about relapse. To select patients with terminal liver disease due to ALD for transplants, most LT centers in the United States and European countries require a 6-month sober period before transplantation. However, Korea has a different social and cultural background than Western countries, and most organ transplants are made from living donors, who account for approximately twice as many procedures as deceased donors. Most LT centers in Korea do not require a specific period of sobriety before transplantation in patients with ALD. As per the literature, 8%–20% of patients resume alcohol consumption 1 year after LT, and this proportion increases to 30%–40% at 5 years post-LT, among which 10%–15% of patients resume heavy drinking. According to previous studies, the risk factors for alcohol relapse after LT are as follows: young age, poor familial and social support, family history of alcohol use disorder, previous history of alcohol-related treatment, shorter abstinence before LT, smoking, psychiatric disorders, irregular follow-up, and unemployment. Recognition of the risk factors, early detection of alcohol consumption after LT, and regular follow-up by a multidisciplinary team are important for improving the short- and long-term outcomes of LT patients with ALD.

Background The level of surgical difficulty in laparoscopic cholecystectomy might be predictable based on preoperative imaging and intraoperative findings indicative of cholecystitis severity. Several scales for laparoscopic cholecystectomy have been developed, but most are complex, unverified, and not widely adopted. This study evaluated the association of the cystic duct fibrosis score (range, 0–3) with surgical difficulty in laparoscopic cholecystectomy. Methods Between July 2018 and November 2018, 163 laparoscopic cholecystectomy cases were retrospectively reviewed at a single center. Patients’ demographics, preoperative laboratory data, operation time, complications, hospital stay, and cholecystitis severity grade were investigated. We also evaluated the associations of the Tokyo Guidelines 2018 and the Parkland grading scale with the cystic fibrosis score. Results The cystic duct fibrosis score was associated with preoperative white blood cells (p

Introduction: This study aimed to compare the prognostic impact of laparoscopic left hepatectomy (LLH) with that of open left hepatectomy (OLH) on patient survival after resection of left hepatocellular carcinoma (HCC). Methods: Among the 953 patients who received initial treatment for primary HCC that was resectable by either LLH or OLH from 2013 to 2017 in Japan and Korea, 146 patients underwent LLH and 807 underwent OLH. The inverse probability of treatment weighting approach based on propensity scoring was used to address the potential selection bias inherent in the recurrence and survival outcomes between the LLH and OLH groups. Results: The occurrence rate of postoperative complications and hepatic decompensation was significantly lower in the LLH group than in the OLH group. Recurrence-free survival (RFS) was better in the LLH group than in the OLH group (hazard ratio, 1.33; 95% confidence interval, 1.03–1.71; p = 0.029), whereas overall survival (OS) were not significantly different. Subgroup analyses of RFS and OS revealed an almost consistent trend in favor of LLH over OLH. In patients with tumor sizes of ≥4.0 cm or those with single tumors, both RFS and OS were significantly better in the LLH group than in the OLH group. Conclusions: LLH decreases the risk of tumor recurrence and improves OS in patients with primary HCC located in the left liver.

Abstract Background To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Methods FLS from RA patients were activated with interleukin (IL)-1β in the presence of increasing concentrations of M808, a novel specific HDAC6 inhibitor. Production of ILs, chemokines, and metalloproteinases (MMPs) was measured in ELISAs. Acetylation of tubulin and expression of ICAM-1 and VCAM-1 were assessed by Western blotting. Wound healing and adhesion assays were performed. Cytoskeletal organization was visualized by immunofluorescence. Finally, the impact of HDAC6 inhibition on the severity of arthritis and joint histology was examined in a murine model of adjuvant-induced arthritis (AIA). Results HDAC6 was selectively inhibited by M808. The HDAC6 inhibitor suppressed the production of MMP-1, MMP-3, IL-6, CCL2, CXCL8, and CXCL10 by RA-FLS in response to IL-1β. Increased acetylation of tubulin was associated with decreased migration of RA-FLS. Inhibiting HDAC6 induced cytoskeletal reorganization in RA-FLS by suppressing the formation of invadopodia following activation with IL-1β. In addition, M808 tended to decrease the expression of ICAM-1 and VCAM-1. In the AIA arthritis model, M808 improved the clinical arthritis score in a dose-dependent manner. Also, HDAC6 inhibition was associated with less severe synovial inflammation and joint destruction. Conclusion Inhibiting HDAC6 dampens the inflammatory and destructive activity of RA-FLS and reduces the severity of arthritis. Thus, targeting HDAC6 has therapeutic potential.

Backgrounds/Aims: Post-hepatectomy liver failure (PHLF) is a major concern for patients with hepatocellular carcinoma (HCC) who have undergone liver resection. The albumin-bilirubin (ALBI) score is a novel model for assessing liver function. We aimed to investigate the effectiveness of the ALBI score as a predictor of PHLF in HCC patients who have undergone hepatectomy in South Korea. Methods: Between January 2014 and November 2018, HCC patients who underwent hepatectomy and indocyanine retention rate at 15 min (ICG-R15) test were enrolled in this study. Results: A total of 101 patients diagnosed with HCC underwent hepatectomy. Thirty-two patients (31.7%) experienced PHLF. The ALBI score (OR 2.83; 95% CI 1.22-6.55; p=0.015), ICG-R15 (OR 1.07; 95% CI 1.02-1.12; p=0.007) and ALBI grade (OR 2,86; 95% CI 1.08-7.58; p=0.035) were identified as independent predictors of PHLF by multivariable analysis. The area under the receiver operating characteristic curve of the ALBI score and ICG-R15 were 0.676 (95% CI 0.566-0.785) and 0.632 (95% CI 0.513-0.752), respectively. The optimal cutoff value of the ALBI score in predicting PHLF was -2.62, with a sensitivity of 75.0% and a specificity of 56.5%. Conclusions: The ALBI score is an effective predictor of PHLF in patients with HCC, and its predictive ability is comparable to that of ICG-R15.

Drug-induced liver injury is the most common cause of acute liver failure in Western countries by prescription drugs and herbal medications. Liver injury due to azithromycin has rarely been reported. This is a brief report of a patient administered azithromycin and who developed acute liver failure leading to liver transplantation. We report the case of a 68-year-old woman who developed jaundice 1 week after she started taking a azithromycin. On the 3rd day of hospitalization, her hepatic function rapidly deteriorated and level of consciousness decreased to drowsiness. The model for end-stage liver disease score was confirmed to be 33, and liver transplantation was considered. On the 8th day of hospitalization, she underwent emergency living donor liver transplantation, receiving a right lobe liver graft from a 35-year-old male donor, the patient’s son. Currently, she is alive with good liver function after 25 months of transplant. This case suggests that azithromycin may cause rare hepatitis with liver failure. Therefore, at the beginning of the azithromycin treatment, patients should visit the hospital immediately if symptoms such as jaundice and abdominal pain are experienced.

Abstract Objectives Histone deacetylase (HDAC) 6 promotes inflammation. We investigated the anti-arthritic effects of CKD-506, a novel HDAC6 inhibitor, in vitro and in a murine model of arthritis as a novel treatment option for rheumatoid arthritis (RA). Methods HDAC6 was overexpressed in mouse peritoneal macrophages and RAW 264.7 cells, and the effects of a HDAC6 inhibitor CKD-506 on cytokine production and activity of NF-κB and AP-1 signaling were examined. Peripheral blood mononuclear cells (PBMCs) from RA patients and fibroblast-like synoviocytes (FLS) were activated in the presence of CKD-506. Next, regulatory T cells (Tregs) were induced from RA patients and co-cultured with healthy effector T cells (Teffs) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis were assessed in a murine model of adjuvant-induced arthritis (AIA). Results Overexpression of HDAC6 induced macrophages to produce TNF-α and IL-6. The inhibitory effect of CKD-506 was mediated via blockade of NF-κB and AP-1 activation. HDAC6 inhibition reduced TNF-α and IL-6 production by activated RA PBMCs. CKD-506 inhibited production of MMP-1, MMP-3, IL-6, and IL-8 by activated FLS. In addition, CKD-506 inhibited proliferation of Teffs directly and indirectly by improving iTreg function. In AIA rats, oral CKD-506 improved clinical arthritis in a dose-dependent manner. A combination of sub-therapeutic CKD-506 and methotrexate exerted a synergistic effect. Conclusion The novel HDAC6 inhibitor CKD-506 suppresses inflammatory responses by monocytes/macrophages, improves Treg function, and ameliorates arthritis severity in a murine model of RA. Thus, CKD-506 might be a novel and effective treatment option for RA.

Background : Most patients who undergo liver transplantation (LT) have advanced cirrhosis and poor nutritional status. The aim of this study was to investigate the effect of enteral nutrition (EN) on the clinical outcomes after LT. Methods : From 2015 to 2019, the medical records of recipient of LT at Kosin University Gospel Hospital were retrospectively reviewed. Results : Thirty-seven patients underwent LT. Nineteen patients underwent living donor liver transplantation (LDLT) and 18 patients underwent deceased donor liver transplantation (DDLT). One LDLT patient was excluded because transplantation was done within 1 month. Five DDLT patients were excluded either because they died within 1 month (n=4) or received transplantation within 1 month. (n=1). Therefore, 31 patients were analyzed. Psoas-muscle index (P=0.715) and serum albumin (P=0.111) were not statistically different between the LDLT and DDLT groups. Four patients (4/31) were readmitted because of infection. One LDLT patient was diagnosed with genitourinary infection. The three DDLT patients were diagnosed with pulmonary tuberculosis (n=1), diverticulitis (n=1), and sepsis (n=1). Readmission caused by infection was not statistically different between LDLD and DDLT patients (P=0.284). Preoperative EN

Abstract Background Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). We investigated the therapeutic effect of a new selective HDAC6 inhibitor, CKD-L, compared to ITF 2357 or Tubastatin A on CIA and regulatory T (Treg) cells in patients with rheumatoid arthritis (RA). Methods CIA was induced by bovine type II collagen (CII) in DBA/1 J mice. Mice were treated with HDAC inhibitor for 18 days. Arthritis score was assessed and histological analysis was performed by hematoxylin and eosin (H&E) stain. Cytotoxic T-lymphocyte associated protein (CTLA)-4 expression in induced Treg cells was analyzed and suppression assay was analyzed using Treg cells and effector T (Teff) cells isolated from naive C57BL/6 mice by flow cytometry. Cytokines were analyzed in peripheral blood mononuclear cells (PBMC) of five patients with RA by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Tumor necrosis factor (TNF) was analyzed using PMA- activated THP-1 cells by ELISA. Suppression assay was analyzed using Treg cells and Teff cells isolated from RA patients by flow cytometry. Results In the CIA model, CKD-L and Tubastatin A significantly decreased the arthritis score. CKD-L increased CTLA-4 expression in Foxp3+ T cells and inhibited the proliferation of Teff cells in the suppression assay. In RA PBMC, CKD-L significantly inhibited TNF and interleukin (IL)-1β, and increased IL-10. CKD-L and Tubastatin A inhibited TNF secretion from PMA-activated THP-1 cells. CKD-L and ITF 2357 inhibited the proliferation of Teff cells in RA patients in the suppression assay. Tubastatin A had no effect on inhibition of proliferation. Conclusion CKD-L decreased the arthritis score in CIA, reduced the expression of TNF and IL-1β, and increased the expression of IL-10 in PBMC from RA patients. CKD-L increased CTLA-4 expression and the suppressive function of Treg cells. These results suggest that CKD-L may have a beneficial effect in the treatment of RA.

An important role for plexinD1 in thymic development is inferred from studies of germline Plxnd1 knockout (KO) mice where mislocalized CD69+ thymocytes as well as ectopic thymic subcapsular medullary structures were observed. Given embryonic lethality of the Plxnd1-/- genotype, fetal liver transplantation was employed in these prior analyses. Such embryonic hematopoietic reconstitution may have transferred Plxnd1 KO endothelial and/or epithelial stem cells in addition to Plxnd1 KO lymphoid progenitors, thereby contributing to that phenotype. Here we use Plxnd1flox/flox mice crossed to pLck-Cre, pKeratin14-Cre or pTek-Cre transgenic animals to create cell-type specific conditional knockout (CKO) lines involving thymocytes (D1ThyCKO), thymic epithelium (D1EpCKO) and thymic endothelium (D1EnCKO), respectively. These CKOs allowed us to directly assess the role of plexinD1 in each lineage. Loss of plexinD1 expression on double positive (DP) thymocytes leads to their aberrant migration and cortical retention after TCR-mediated positive selection. In contrast, ectopic medulla formation is a consequence of loss of plexinD1 expression on endothelial cells, in turn linked to dysregulation of thymic angiogenesis. D1EpCKO thymi manifest neither abnormality. Collectively, our findings underscore the non-redundant roles for plexinD1 on thymocytes and endothelium, including the dynamic nature of medulla formation resulting from crosstalk between these thymic cellular components.

The underlying cause of the enigmatic coexistence of immunodeficiency and autoimmune disorders in patients with primary immunodeficiency such as Omenn syndrome is largely due to the inefficient negative selection within thymus where T cells develop. Recent advances in molecular biology and animal models answered one of the key questions on the relationship between the partially impaired T cell development at early stages and the presence of autoreactive T cells in periphery. T cell development and thymic organogenesis are tightly coupled to each other. The maturing T cells induce thymic epithelial cell development and AIRE (Autoimmune regulator) expression in thymic medullary epithelial cells. Without thymic medullary epithelial cells and AIRE protein in the patients with primary immunodeficiency, a few autoreactive T cells survive through the complete thymic selection processes and expand to form oligoclonal T cell pools in the periphery. The induction of thymic medullary epithelial cell development may be considered as an alternative therapeutic approach in addition to the current standard therapy for primary immunodeficiency - stem cell transplantation. [ABSTRACT FROM AUTHOR]

Hwang S, Lee S-G, Ahn C-S, Kim K-H, Moon D-B, Ha T-Y, Song G-W, Jung D-H, Choi N-K, Kim K-W, Yu Y-D, Park G-C, Park P-J, Choi Y-I. A clinical assessment of mycophenolate drug monitoring after liver transplantation. Clin Transplant 2010 DOI: 10.1111/j.1399-0012.2009.01166.x © 2010 John Wiley & Sons A/S. Recent findings have suggested the clinical utility of therapeutic drug monitoring (TDM) in patients treated with mycophenolate mofetil (MMF). Aim: To assess whether routine mycophenolic acid (MPA) TDM is beneficial and how to utilize it. Methods: A series of short-term prospective studies on TDM for MPA and/or tacrolimus was performed at a large-volume center. Results: The 673 adult liver transplants were divided into four groups based on immunosuppressive regimens as tacrolimus monotherapy (n = 369), tacrolimus–MMF therapy (n = 270), MMF-minimal tacrolimus therapy (n = 17), and MMF monotherapy (n = 17). There was a significant difference of tacrolimus concentration between the groups receiving tacrolimus monotherapy and tacrolimus–MMF therapy during the first two yr (at two yr: 8.4 ± 2.7 vs. 6.3 ± 2.6 ng/mL; p ≤ 0.002). MMF-minimal tacrolimus therapy and MMF monotherapy were applied after first three months and MPA levels ranged from 1.8 to 5.3 μg/mL. Correlation between MMF dosage and MPA concentration showed wide interindividual variations (n = 304, r2 = 0.271, p < 0.001), in which r2 was fluctuating from 0.056 to 0.213 according to the post-transplant period over five yr; wide intraindividual variation was also observed during the first two months (n = 12, r2 < 0.2, p > 0.195). About 10% of patients were classified as poor MMF absorber and excluded from MMF usage. Mean MPA level leading to successful MMF monotherapy or MMF-minimal tacrolimus therapy was ≥1.0 μg/mL in 87% and >2.0 μg/mL in 56.5%. Conclusion: MPA TDM-based MMF dosage adjustment enabled us to administer MMF more confidently than categorical dosing. MPA TDM appears to be a useful tool to cope with the wide pharmacokinetic variability of MMF after liver transplantation. [ABSTRACT FROM AUTHOR]

Background/Aims Most patients who undergo liver transplantation (LT) have advanced cirrhosis and poor nutritional status. The aim of this study was to investigate the effect of nutritional status on the incidence of complications after LT and the effect of oral nutrition on LT outcomes. Methods From January 2015 to May 2019, the medical records of patients who underwent LT at Kosin University Gospel Hospital were retrospectively reviewed, focusing on nutritional status, perioperative enteral nutrition, and readmission due to infection within 3 months of LT. Results A total of 37 patients underwent LT. Nineteen patients underwent living donor liver transplantation (LDLT) and 18 patients underwent deceased donor liver transplantation (DDLT). One LDLT patient was excluded because follow-up was less than 3 months. Five DDLT patients were excluded either because they died within 1 month (n=4) or were followed up for less than 3 months (n=1). Therefore, 31 patients were analyzed. Baseline Model for End Stage Liver Disease score (p=0.001), prothrombin time international normalized ratio (p=0.028), and serum creatinine (p=0.006) were statistically different between the LDLT and DDLT groups. However, psoas-muscle index (p=0.840) and serum albumin (p=0.111) were not different. Four patients (4/31) were readmitted because of infection. One LDLT patient was diagnosed with genitourinary infection. The three DDLT patients were diagnosed with pulmonary tuberculosis (n=1), diverticulitis (n=1), and sepsis (n=1). Readmission caused by infection was not statistically different between LDLD and DDLT patients (p=0.284). Preoperative enteral nutrition <25% of the recommended amount (p=0.016) was significantly associated with readmission related to infection. In multivariate analyses, pre-operative enteral nutrition <25% was an independent risk factor for readmission due to infection after LT regardless of psoas-muscle index, baseline Model for End Stage Liver Disease score, or LT type. Conclusions Preoperative poor enteral nutrition is significantly associated with readmission risk due to infection within 3 months of LT. [ABSTRACT FROM AUTHOR]