Anticancer Effect of Statins in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma.

The anticancer effect of statins is drawing attention. However, it is unclear whether statin use reduces the risk of hepatocellular carcinoma (HCC) recurrence in patients who undergo liver transplantation (LT) for HCC. Consecutive patients who underwent LT for HCC between 1995 and 2019 were enrolled. The effects of statins on HCC recurrence and mortality were compared between statin user and statin nonuser groups. We performed the analyses in a variety of ways, including inverse probability treatment weighting (IPTW) methods to balance any confounders and the landmark method to avoid immortal time bias. A total of 430 patients were enrolled, among whom 323 (75.1%) were statin nonusers and 107 (24.9%) were statin users. During a median of 64.9 months (IQR, 26.1-122.6 months) of follow-up, 79 patients (18.4%) had HCC recurrence and 111 (25.8%) died. Among those who died, 53 (47.7%) were identified as HCC-related mortalities. Statin use was a predictor of HCC recurrence (adjusted hazard ratio [HR], 0.3; 95% confidence interval [CI], 0.1-0.6; P = 0.002), all-cause mortality (adjusted HR, 0.3; 95% CI, 0.2-0.5; P < 0.001), and HCC-related mortality (adjusted HR, 0.4; 95% CI, 0.2-0.9; P = 0.03). The effects of statin use on clinical outcomes were also identified through IPTW analysis. There was a dose-dependent relationship between statin use and HCC recurrence. The anticancer effect of statins on HCC recurrence was consistently significant across multivariable-stratified and sensitivity analyses. Statin use significantly reduced the risk of HCC recurrence and improved the survival of patients who underwent LT for HCC.

Differential mGluR5 expression in response to the same stress causes individually adapted hippocampal network activity.

Individual differences in stress vulnerability and resilience have been observed even within a single cohort of inbred rats or mice. Stress phenotypes are typically quantified as changes in the behavior of experimental animals, which is the outcome of altered electrical activity of the brain network. Although mGluR5 is associated with individual vulnerability to stress and can act as a sensitive biomarker of stress adaptation, our understanding of mGluR5-dependent modifications to neural network activities in vivo remains limited. Here, we examined individual rats for changes in hippocampal mGluR5 expression induced by restraint stress and found that these changes cause accompanying changes in hippocampal electroencephalography (EEG) activity. We found six days of restraint stress caused variable changes in hippocampal mGluR5 expression, ranging from 20.9% to 210.7% of the control group. The low mGluR5 protein group (LE) showed increased methylation of the mGluR5 CpG island, reduced mGluR5 mRNA levels, and unaltered basal EEG theta spectral power between stress day 1 and 6. In contrast, the high mGluR5 protein group (HE) showed reduced methylation of CpG sites, increased mGluR5 mRNA expression, and reduced basal theta spectral power on stress day 6. We also found that injection of lentiviruses expressing mGluR5-specific shRNAs into the hippocampus rescued this reduction in baseline theta power in HE rats. These data suggest a causal relationship between individual differences in the changes in hippocampal mGluR5 expression induced by repetitive restraint stress and the accompanying changes in ensemble neural activity in the hippocampus.

Clinical Course of Hepatic Artery Thrombosis After Living Donor Liver Transplantation Using the Right Lobe.

Hepatic artery thrombosis (HAT) can result in biliary tree necrosis and graft loss, necessitating retransplantation. The most effective treatment approach is still controversial. This study was performed to review the outcomes of HAT after living donor liver transplantation (LDLT) and to clarify the feasibility of different strategies. From May 1996 to August 2017, LDLT using the right lobe was performed in 827 adult patients in our center. Our technique of hepatic artery (HA) reconstruction is end-to-end anastomosis under a microscope (10×). Diagnosis of HAT was performed using Doppler sonography and computed tomography (CT) angiography. HAT was initially treated with surgical or endovascular procedure, and retransplantation was considered according to the graft condition. Among the 827 cases of LDLT using the right lobe, HAT occurred in 16 (1.9%) cases within 1 month after transplantation. Within the first week, 7 of these HAT cases (43.8%) occurred (early HAT), while the remaining 9 cases (56.2%) occurred between the first week and 1 month (late HAT). The incidence of graft failure was high in early HAT (42.9%), and the frequency of biliary complications was high in late HAT (77.8%). The success rate of HA recanalization was 62.5% (10/16): 100% (5/5) after reoperation and 45.5% (5/11) after the endovascular procedure. Of the patients in whom treatment failed in late HAT (n = 5), 4 underwent neovascularization during observation. A total of 5 patients underwent graft failure, and 3 of these patients underwent repeat liver transplantation (LT). Mortality occurred in 3 patients, including 1 in the surgical group and 2 in the endovascular group. In conclusion, early diagnosis and aggressive treatment of HAT are necessary to avoid graft failure, and the choice of treatment depends on various factors. Although further studies are required, early HAT requires preparation for graft failure, while late HAT requires treatment for biliary complications.

Deep gray matter iron measurement in patients with liver cirrhosis using quantitative susceptibility mapping: Relationship with pallidal T1 hyperintensity.

BACKGROUND: The liver is a central organ for the metabolism of iron and manganese and the places where those metals are commonly deposited overlap in the brain. PURPOSE/HYPOTHESIS: To elucidate the relationship between pallidal T1 hyperintensity and iron deposition in the deep gray matter of liver cirrhosis patients using quantitative susceptibility mapping (QSM). STUDY TYPE: Retrospective case-control study SUBJECTS: In all, 38 consecutive liver cirrhosis patients who received brain magnetic resonance imaging (MRI) as pretransplant evaluation. FIELD STRENGTH/SEQUENCE: QSM was reconstructed from 3D multi- or single-echo phase images at 3T. T1 -weighted images were used for the assessment of pallidal hyperintensity and pallidal index (PI). ASSESSMENT: Patients were divided into two groups according to the presence of pallidal hyperintensity by consensus of two radiologists. Susceptibility values were acquired for five deep gray matter structures. STATISTICAL TEST: QSM measures were compared between two groups using the t-test. We also calculated Pearson correlations between QSM measures and PI. RESULTS: In all, 26 patients showed pallidal hyperintensity (T1 h group) and 12 did not (T1 n group). The susceptibility of the globus pallidus (GP) in the T1 h group (120.6 ± 38.1 ppb) was significantly lower than that in the T1 n group (150.0 ± 35.2, P = 0.030). The susceptibility of the dentate nucleus (DN) in the T1 h group (88.1 ± 31.0) was significantly lower than that in the T1 n group (125.6 ± 30.6, P = 0.001). Negative correlation between the susceptibility of GP (r = -0.37, P = 0.022) and the PI, and between DN (r = -0.43, P < 0.001) and the PI was found. DATA CONCLUSION: Liver cirrhosis patients with pallidal T1 hyperintensity had lower susceptibility values in the GP and DN than those without it. This suggests a possible interaction between iron and manganese in the brains of liver cirrhosis patients. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1342-1349.

Prognostic Prediction Models for Resection of Large Hepatocellular Carcinoma: A Korean Multicenter Study.

BACKGROUND: We developed a prognostic prediction model (PPM) using 4 factors for hepatic resection (HR) of large hepatic cellular carcinoma (HCC). Multiplication of α-fetoprotein (AFP), des-γ-carboxy prothrombin, and tumor volume (TV) (ADV score) is a surrogate marker for post-resection prognosis. This study intended to validate the predictive power of 4-factor PPM and to develop new ADV score-based PPM. METHODS: A total of 526 patients who underwent HR for solitary HCC ≥ 8 cm were selected from 9 Korean institutions between 2008 and 2014. RESULTS: Median tumor diameter and TV were 11.0 cm and 398 mL, respectively. Tumor recurrence and patient survival rates were 53.0 and 78.4% at 1 year and 70.2 and 49.3% at 5 years, respectively. Independent risk factors for both tumor recurrence and patient survival included AFP ≥ 100 ng/mL, hypermetabolic FDG-positron emission tomography (PET), microvascular invasion and satellite nodules, which comprised 4 factors of the PPM. Five subgroups based on the number of involved risk factors exhibited significant differences in tumor recurrence and patient survival. ADV score cutoff was set at 7log (ADV7log) after cluster prognostic analysis. Patient grouping according to combination of ADV7log and FDG-PET findings (ADV7log-PET) exhibited significant differences in tumor recurrence and patient survival, comparable to those of the 4-factor PPM. CONCLUSIONS: Two PPMs using 4 risk factors and ADV7log-PET could reliably predict the risk of early HCC recurrence and long-term survival outcomes in patients who underwent HR for large HCC. We believe that these PPMs can guide surgical treatment for large HCCs from preoperative HR planning to post-resection follow-up.

Glutamatergic stimulation of the left dentate gyrus abolishes depressive-like behaviors in a rat learned helplessness paradigm.

BACKGROUND: Episodic experiences of stress have been identified as the leading cause of major depressive disorder (MDD). The occurrence of MDD is profoundly influenced by the individual's coping strategy, rather than the severity of the stress itself. Resting brain activity has been shown to alter in several mental disorders. However, the functional relationship between resting brain activity and coping strategies has not yet been studied. In the present study, we observed different patterns of resting brain activity in rats that had determined either positive (resilient to stress) or negative (vulnerable to stress) coping strategies, and examined whether modulation of the preset resting brain activity could influence the behavioral phenotype associated with negative coping strategy (i.e., depressive-like behaviors). METHODS: We used a learned helplessness paradigm-a well-established model of MDD-to detect coping strategies. Differences in resting state brain activity between animals with positive and negative coping strategies were assessed using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glutamatergic stimulation was used to modulate resting brain activity. RESULTS: After exposure to repeated uncontrollable stress, seven of 23 rats exhibited positive coping strategies, while eight of 23 rats exhibited negative coping strategies. Increased resting brain activity was observed only in the left ventral dentate gyrus of the positive coping rats using FDG-PET. Furthermore, glutamatergic stimulation of the left dentate gyrus abolished depressive-like behaviors in rats with negative coping strategies. CONCLUSION: Increased resting brain activity in the left ventral dentate gyrus helps animals to select positive coping strategies in response to future stress.

The clinical outcomes of patients with portal vein tumor thrombi after living donor liver transplantation.

The purpose of this study was to evaluate the feasibility of living donor liver transplantation for treatment of patients with hepatocellular carcinoma and segmental portal vein tumor thrombus (PVTT) below the second-order branch. Between January 2005 and December 2015, we retrospectively analyzed 242 patients in a control group (n = 184), a microvascular invasion (MVI) group (n = 24), and a PVTT group (n = 34). To assess the risks associated with PVTT, we evaluated recurrence, the disease-free survival (DFS) rate, the overall survival (OS) rate, and various other factors based on the characteristics of patients and tumors. Of the 242 patients, 5-year DFS and OS rates were 79.5% and 70.7%. A total of 34 (14.0%) patients had PVTT, of whom 7 had lobar PVTT in first-order branches. The control, MVI, and PVTT groups significantly differed in terms of tumor morphology (maximal and total diameters) and biology (alpha-fetoprotein [AFP] and protein induced by vitamin K absence or antagonist II). The control, MVI, and PVTT groups significantly differed in terms of the recurrence, DFS, and OS rates. Especially, lobar PVTT reduced the 5-year DFS and OS rates to dismal and 14.3%, respectively, but segmental PVTT was associated with favorable 5-year DFS and OS rates (63.9% and 50.3%, respectively). We found no statistically significant difference in the DFS and OS rates of patients with MVI alone and segmental PVTT alone. In patients in the segmental PVTT group with AFP levels of <100 ng/mL, the 5-year DFS and OS rates were 90.9% and 71.3%, respectively. In conclusion, a tumor thrombus in a lobar portal vein remains a contraindication to liver transplantation. However, a segmental PVTT is acceptable, especially when the AFP level is <100 ng/mL. Liver Transplantation 23 1023-1031 2017 AASLD.

Immunohistochemical markers for hepatocellular carcinoma prognosis after liver resection and liver transplantation.

AIM: There were differences in progression and prognosis of hepatocellular carcinoma (HCC) after surgery between liver resection (LR) and liver transplantation (LT). In this study, immunohistochemical (IHC) markers associated with the prognosis of HCC were assessed. METHODS: Data were collected from 167 patients who underwent LT (n=41) or LR (n=126) for HCC. IHC markers including alpha-fetoprotein (AFP), p53, Ki-67, cytokeratin 7 (CK7), and cytokeratin 19 (CK19) were compared between the treatment methods in tumor tissue. RESULTS: AFP- and p53-negative patients had a significantly higher survival rate than AFP- and p53-positive patients (AFP: disease-free survival [DFS] P=.006, overall survival [OS] P=.016; p53: DFS P=.005, OS P=.038) in the LR group. CK19 was related to DFS (P=.005), while CK7 (P=.014) and CK19 (P=.06) were related to OS in the LT group. When we combined factors that were significant in both groups (LR: AFP and p53, LT: CK7 and CK19), all-negative patients had a higher survival rate (LR: DFS P=.025, OS P=.043, LT: DFS P=.034, OS P=.008). CONCLUSION: p53 and AFP were predictors for poor prognosis of HCC after LR; CK7 and CK19 could be predictors for poor prognosis of patients with HCC after LT.

Performance of Gadoxetic Acid-Enhanced Liver Magnetic Resonance Imaging for Predicting Patient Eligibility for Liver Transplantation Based on the Milan Criteria.

PURPOSE: This study aimed to evaluate the accuracy of gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) in predicting eligibility for liver transplantation in patients with hepatocellular carcinoma (HCC) based on Milan criteria (MC). MATERIALS AND METHODS: We reviewed Gd-EOB-MRI of 44 patients who underwent liver transplantation for HCC with cirrhosis for the presence/size of HCCs, vascular invasion, and transplant eligibility based on MC. Hepatocellular carcinoma was diagnosed based on conventional radiological hallmarks (arterial enhancement and washout) or the modified criteria. RESULTS: Among 44 patients, 16 was beyond MC. Sensitivity, specificity, and accuracy of conventional radiological hallmark and the modified criteria for predicting eligibility by MC were 31.3%, 96.3%, and 72.7%, and 68.8%, 96.3%, and 86.4%, respectively. CONCLUSIONS: Gd-EOB-MRI showed high specificity but poor sensitivity for assessing transplant eligibility based on MC when adopting the conventional radiological hallmarks of HCC. Our modified criteria showed significantly better sensitivity and accuracy than the conventional radiological hallmarks.

Effects of sling exercise on postural sway in post-stroke patients.

[Purpose] To examine the effects of sling exercise on the balance of post-stroke patients. [Subjects and Methods] A total of 18 post-stroke patients (13 men; mean age, 55.3 years) were recruited, and randomly assigned them into sling exercise (n=10) and control exercise (n=8) groups. The Good Balance System was used for measurement of velocity (anteroposterior and mediolateral, mm/s), velocity moment (mm2/s) of the movement of the center of pressure, and distance (anteroposterior and mediolateral, mm) between the center of pressure and the center point. The changes in mediolateral velocity, anteroposterior velocity, and velocity moment were compared between two groups in addition to the comparison of distance between the center of pressure and the center point of postural sway. [Results] The sling exercise group showed more significant improvements in anteroposterior velocity, mediolateral velocity, velocity moment, anteroposterior distance, and mediolateral distance than the control exercise group. [Conclusion] Sling exercise improved post-stroke balance performance and could be used as a therapeutic strategy to improve post-stroke functional recovery.

CXXC5 plays a role as a transcription activator for myelin genes on oligodendrocyte differentiation.

Myelination in corpus callosum plays important role for normal brain functions by transferring neurological information between various brain regions. However, the factors controlling expression of myelin genes in myelination are poorly understood. Here, CXXC5, a recently identified protein with CXXC-type zinc finger DNA binding motif, was characterized as a transcriptional activator of major myelin genes. We identified expression of CXXC5 expression was increased by Wnt/ß-catenin signaling. CXXC5 specifically expressed in the white matter induced expression of myelin genes through the direct binding of CXXC DNA-binding motif of CXXC5 on the MBP promoter. During the differentiation of neural stem cells (NSCs) of CXXC5(-/-) mice, the expressions of myelin genes were simultaneously reduced. The CXXC5(-/-) mice exhibited severely reduction of myelin genes expression in corpus callosum as well as abnormalities in myelin structure. The disrupted structural integrity of myelin in the CXXC5(-/-) mice resulted in reduced electrical conduction amplitudes at corpus callosum. These findings indicate that the regulation of myelin genes expression by CXXC5 is important for forming myelin structure involved with axonal electrical signal transfer in the corpus callosum.

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases.

The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory-inhibitory balance.

Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system.

Depression frequently accompanies in Parkinson's disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6-hydroxydopamine (6-OHDA) lesioned and sham operated rats: [(18) F]FP-CIT for DA transporters and [(18) F]Mefway for serotonin 1A (5-HT(1A)) receptors. Here, 6-OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region-of-interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5-HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6-OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R(2) = 0.79, P = 0.003). In 6-OHDA lesioned rats, binding values for 5-HT(1A) receptors was 22% lower than the sham operated group. This decrement of 5-HT(1A) receptor binding was also correlated with the severity of depression (R(2) = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior.

B-cell-associated immune profiles in patients with decompensated cirrhosis.

OBJECTIVE: Previous observations on immune dysfunction in decompensated cirrhosis have raised the possibility of B-cell impairment. METHODS: B-cell subsets in decompensated cirrhotic patients were investigated. Twenty-six decompensated cirrhotic patients and 26 healthy controls were included in this study. The percentages of B-cell subsets, such as mature, memory, immature B cells, and interleukin (IL)-10+-B-cell subpopulations, were measured using fluorescent activated cell sorting. B-cell-associated cytokines (IL-10, IL-21 and IL-4) were determined using an enzyme-linked immunosorbent assay. RESULTS: The percentage of total B cells and mature B cells increased in patients with decompensated cirrhosis compared to healthy controls. The proportions of memory B cells were significantly lower in the decompensated cirrhosis group than the control group. However, the frequency of immature B cells and the percentage of IL-10-expressing cells that were CD19+, memory, mature, or immature B cells were not significantly different between the two groups. Serum levels of IL-10, IL-21, and IL-4 were significantly lower in the decompensated cirrhosis group compared to the control group. CONCLUSION: These results indicate significant alterations in peripheral blood B-cell subsets in patients with decompensated cirrhosis. Specifically, a profound reduction of memory B cells was observed in spite of an increase in total B-cell populations in decompensated cirrhotic patients. This implies the underlying mechanisms of impaired immune response in these patients.

Lupeol Protects Against Cerulein-Induced Acute Pancreatitis in Mice.

Lupeol is a triterpenoid commonly found in fruits and vegetables and is known to exhibit a wide range of biological activities, including antiinflammatory and anti-cancer effects. However, the effects of lupeol on acute pancreatitis specifically have not been well characterized. Here, we investigated the effects of lupeol on cerulein-induced acute pancreatitis in mice. Acute pancreatitis was induced via an intraperitoneal injection of cerulein (50 µg/kg). In the lupeol treatment group, lupeol was administered intraperitoneally (10, 25, or 50 mg/kg) 1 h before the first cerulein injection. Blood samples were taken to determine serum cytokine and amylase levels. The pancreas was rapidly removed for morphological examination and used in the myeloperoxidase assay, trypsin activity assay, and real-time reverse transcription polymerase chain reaction. In addition, we isolated pancreatic acinar cells using a collagenase method to examine the acinar cell viability. Lupeol administration significantly attenuated the severity of pancreatitis, as was shown by reduced pancreatic edema, and neutrophil infiltration. In addition, lupeol inhibited elevation of digestive enzymes and cytokine levels, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and interleukin (IL)-6. Furthermore, lupeol inhibited the cerulein-induced acinar cell death. In conclusion, these results suggest that lupeol exhibits protective effects on cerulein-induced acute pancreatitis.

Translational possibility of [18 F]Mefway to image serotonin 1A receptors in humans: Comparison with [18 F]FCWAY in rodents.

PURPOSE: To compare the cerebral uptake and binding potential of [18 F]FCWAY and [18 F]Mefway in the rodent to assess their potential for imaging serotonin 1A (5-HT1A ) receptors. MATERIALS AND METHODS: In vitro liver microsomal studies were performed to evaluate the degree of defluorination. Dynamic positron emission tomography (PET) studies were then conducted for 2 h with or without an anti-defluorination agent. The regions of interest were the hippocampus and frontal cortex (5-HT1A target regions) and the cerebellum (5-HT1A nontarget region). The in vivo kinetics of the radioligands were compared based on the brain uptake values and target-to-nontarget ratio. We also performed a comparison of binding potential (BPND ) as a steady-state binding parameter. Finally, binding affinities to 5-HT1A receptors were assessed in Chinese hamster ovary cells (CHO-K1) cells expressing human recombinant 5-HT1A receptors. RESULTS: The radiochemical yield of [18 F]Mefway was slightly higher than that of [18 F]FCWAY (19 vs. 15%). With regard to metabolic stability against defluorination, both compounds exhibited similar stability in rat liver microsomes, but [18 F]Mefway displayed higher stability in the human microsome (defluorination ratio at 30 min: 32 vs. 29 in rat liver microsomes, 31 vs. 64 in human liver microsomes for [18 F]Mefway and [18 F]FCWAY, respectively). There were no significant differences in brain uptake, the target-to-nontarget ratios, and the BPND (at hippocampus, peak brain uptakes: 6.9 vs. 8.5, target-to-nontarget ratios: 6.9 vs. 8.5, BPND : 5.2 vs. 6.2 for [18 F]Mefway and [18 F]FCWAY). The binding affinity of [18 F]Mefway was considerably higher than that of [18 F]FCWAY (IC50 : 1.5 nM vs. 2.2 nM). CONCLUSION: [18 F]Mefway exhibits favorable characteristics compared to [18 F]FCWAY in rodents, and may be a promising radioligand for use in human subjects. Synapse 68:595-603, 2014. © 2014 Wiley Periodicals, Inc.

Acute physical stress induces the alteration of the serotonin 1A receptor density in the hippocampus.

Stress affects the serotonergic system, which is associated with depression. Previous research has showed that chronic stress causes the deactivation of the limbic system. However, the influence of the acute physical stress on the serotonergic system in vivo was primarily unclear. The purpose of this research is to elucidate the effects of the acute physical stress in vivo using PET. For quantification of the 5-HT1A receptors in the brain, we measured [(18)F]Mefway uptake in the two experiment groups (control and despair rats). The despair group was subjected to the external stressful situation (i.e., forced swimming) and total duration time of immobility, refers to the despair severity, and was analyzed. In the intercomparison experiment, the resulting PET images of [(18)F]Mefway in the despair rat displayed a significant reduction of radioactivity in the hippocampus (HP) compared with the control. The nondisplaceable binding potential (BPND ) refers to the ratio of the concentration of radioligand in the receptor-rich region (i.e., HP) to the concentration of that in the receptor-free region (i.e., cerebellum). The hippocampal uptake and the BPND in the despair group were respectively about 25 and 18% lower than those of the control group. The ratio of specific binding to nonspecific binding in the despair group was 18% lower than that of the control. In the intracomparison experiments, the BPND and immobility in the despair group showed a strong negative correlation. Taken together, the data illustrates that an acute physical stress induces the change in the serotonergic system that correlates with the behavioral despair.

Prevention and risk factors of hepatitis B recurrence after living donor liver transplantation.

BACKGROUND AND AIM: Without effective prophylaxis, liver transplantation (LT) for hepatitis B virus (HBV)-related liver disease is frequently complicated by severe and rapidly progressive HBV recurrence. The combination of low-dose hepatitis B immunoglobulin (HBIG) and the new nucleos(t)ide analog, entecavir, as prophylaxis for HBV recurrence after living-donor LT (LDLT) were analyzed. METHODS: A total of 315 patients with positive hepatitis B surface antigen underwent LDLT at our transplant center between July 2003 and December 2011. Our protocol for post-transplantation HBV prophylaxis was a combination of low-dose HBIG and nucleos(t)ide analog. RESULTS: During a median follow-up period of 49 months post-transplant, 10 patients (3.2%) had HBV recurrence, which was significantly related to hepatocellular carcinoma (HCC) at transplantation (P = 0.041) and post-LT antiviral agent (P < 0.001) in multivariate analysis. The level of HBV DNA and hepatitis B e antigen state at transplantation were not significant factors for HBV recurrence (P = 0.342 and P = 0.802, respectively). In 170 patients with HCC at LDLT, HCC recurrence was significantly related to HBV recurrence (P < 0.001). Among 10 patients with HBV recurrence, three are alive and two had lost hepatitis B surface antigen. The remaining seven patients died of HCC recurrence. CONCLUSIONS: The combination of low-dose HBIG and nucleos(t)ide analogs is safe and effective for HBV prophylaxis after LDLT. As a post-LT antiviral treatment, entecavir is more effective than lamivudine. HCC at transplantation was significantly associated with HBV recurrence. HBV-related HCC patients who undergo LDLT require close virological monitoring.

Interventional treatment of a biliary stricture after adult right-lobe living-donor liver transplantation with duct-to-duct anastomosis.

BACKGROUND: [corrected] A biliary stricture is the most common complication after living-donor liver transplantation (LDLT). The present study was performed to examine treatment methods and outcomes after treatment for a biliary stricture after LDLT. METHODS AND RESULTS: From January 2000 to December 2010, 488 patients underwent LDLT using the right lobe with duct-to-duct anastomosis at our transplantation centre. Overall biliary strictures were detected in 160 patients (32.8%), and the majority occurred within 2 years after LDLT. Biliary strictures were related to bile leakage (P < 0.001) and the urgency of the surgery (P = 0.012) in a multivariate analysis. All biliary strictures were treated with interventional modalities including an endoscopic or a percutaneous approach. Failure of interventional treatment was demonstrated in 13 patients (8.5%), among them, four (2.6%) underwent re-transplantation and nine (5.9%) died of sepsis and biliary cirrhosis during the follow-up period. A biliary stricture was not related to the survival rate (P = 0.586). CONCLUSION: The incidence of overall biliary stricture was related to bile leakage and the urgency of the surgery. All biliary strictures could be treated by interventional modalities. These approaches are effective, complementary and help to avoid the need for surgery for a biliary stricture.

PKC phosphorylation regulates mGluR5 trafficking by enhancing binding of Siah-1A.

Glutamate is the major excitatory neurotransmitter in the mammalian CNS and acts on both ionotropic and metabotropic glutamate receptors (mGluRs). The mGluRs are widely distributed in the CNS and modulate a variety of neuronal processes, including neurotransmitter release and ion channel function. In hippocampus and cortex, mGluR5 is highly expressed and plays an important role in the regulation of synaptic plasticity. Calmodulin (CaM) binding dynamically regulates mGluR5 surface expression; however, the mechanisms linking CaM to mGluR5 trafficking are not clear. Recent studies showed that CaM binding to mGluR7 regulates its trafficking in a phosphorylation-dependent manner by disrupting the binding of protein interacting with C kinase 1. The E3 ligase seven in absentia homolog (Siah)-1A binds to mGluR5 and competes with CaM binding, making it an intriguing molecule to regulate phosphorylation-dependent trafficking of mGluR5. In the present study, we find that CaM competes with Siah-1A for mGluR5 binding in a phosphorylation-dependent manner in rat hippocampal neurons. Specifically, phosphorylation of mGluR5 S901 favors Siah-1A binding by displacing CaM. We identified critical residues regulating Siah-1A binding to mGluR5 and showed that binding is essential for the Siah-1A effects on mGluR5 trafficking. Siah-1A binding decreases mGluR5 surface expression and increases endosomal trafficking and lysosomal degradation of mGluR5. Thus CaM-regulated Siah-1A binding to mGluR5 dynamically regulates mGluR5 trafficking. These findings support a conserved role for CaM in regulating mGluR trafficking by PKC-dependent regulation of receptor-binding proteins.