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5-Fluorouracil (5-FU) is a chemotherapeutic drug with a good anti-cancer effect on various types of cancers, such as colorectal cancer and breast cancer. However, previous studies have found that 5-FU could induce cognitive deficit in clinics. As ganoderic acid, isolated from Ganoderma lucidum, has a protective effect on neurons, this study investigated the effects of ganoderic acid (GA) against 5-FU-induced cognitive dysfunction with a series of behavioral tests and related indicators. Experimental results showed that GA significantly prevented the reduction of spatial and non-spatial memory in 5-FU-treated mice. In addition, GA not only ameliorated the damage to hippocampal neurons and mitochondrial structure, but also significantly improved abnormal protein expression of mitochondrial biogenesis related marker PGC-1α, and mitochondrial dynamics related markers MFN2, DRP1 and FIS1 in the hippocampi of 5-FU-treated mice. Moreover, GA could up-regulate the expression of neuronal survival and growth-related proteins, such as BDNF, p-ERK, p-CREB, p-Akt, p-GSK3β, Nrf2, p-mTOR, and p-S6, in the hippocampi of 5-FU-treated mice. These results suggest that GA could prevent cognitive dysfunction in mice treated with 5-FU via preventing mitochondrial impairment and enhancing neuronal survival and growth, which provide evidence for GA as a promising adjunctive therapy for chemotherapy related cognitive impairment in clinics.

Chemotherapy-related fatigue (CRF) is increasingly being recognized as one of the severe symptoms in patients undergoing chemotherapy, which not only largely reduces the quality of life in patients, but also diminishes their physical and social function. At present, there is no effective drug for preventing and treating CRF. Ganoderic acid (GA), isolated from traditional Chinese medicine Ganoderma lucidum, has shown a variety of pharmacological activities such as anti-tumor, anti-inflammation, immunoregulation, etc. In this study, we investigated whether GA possessed anti-fatigue activity against CRF. CT26 tumor-bearing mice were treated with 5-fluorouracil (5-FU, 30 mg/kg) and GA (50 mg/kg) alone or in combination for 18 days. Peripheral and central fatigue-related behaviors, energy metabolism and inflammatory factors were assessed. We demonstrated that co-administration of GA ameliorated 5-FU-induced peripheral muscle fatigue-like behavior via improving muscle quality and mitochondria function, increasing glycogen content and ATP production, reducing lactic acid content and LDH activity, and inhibiting p-AMPK, IL-6 and TNF-α expression in skeletal muscle. Co-administration of GA also retarded the 5-FU-induced central fatigue-like behavior accompanied by down-regulating the expression of IL-6, iNOS and COX2 in the hippocampus through inhibiting TLR4/Myd88/NF-κB pathway. These results suggest that GA could attenuate 5-FU-induced peripheral and central fatigue in tumor-bearing mice, which provides evidence for GA as a potential drug for treatment of CRF in clinic.

Compared with weekday admissions, weekend admissions are consistently associated with worse patient outcomes, known as the "weekend effect." The weekend effect may have adverse health consequences, including death. To determine the potential impact of the weekend effect on primary (ie, mortality) and secondary outcomes of patients with upper gastrointestinal hemorrhage (UGIH).This was a network meta-analysis based on cohort studies. Databases were searched for studies published up to April 2018. The predefined primary outcome was mortality (30-d mortality and in-hospital mortality). The secondary efficacy outcomes were rebleeding rates, use of endoscopic therapy, need for surgery or angiography, mean length of hospital stay, and time to endoscopy. The study protocol was registered with PROSPERO (No. CRD42018094660).In total, 25 studies, including 28 analyses (N=1,203,202 patients), were eligible. The results revealed a tendency toward increased 30-day mortality and increased in-hospital mortality among weekend admissions. In a subgroup analysis, there were significance differences in mortality according to the study location (ie, Europe) and UGIH type (ie, variceal UGIH), with these subgroups having elevated mortality rates. Moreover, weekday admissions were associated with a significant decrease in rebleeding rates. In the network meta-analysis, the study location (in Europe or Asia) and type of UGIH (ie, variceal UGIH) were associated with an increased likelihood of high in-hospital mortality among weekend admissions.The evidence derived from this network meta-analysis supports the idea that weekend admissions are associated with an increased risk of death, especially among variceal UGIH patients in European hospitals.

In order to improve the performance of aero engines, trying to increase the turbine inlet temperature is an important way. But the turbine inlet temperature of modern aero engines can be more than 2000 K, which is far more than what the materials can bear. So advanced cooling technologies should be introduced to solve this problem. Using the conjugate heat transfer method, this paper researched the aerodynamic characteristics of a certain turbine blade with complex cooling structures. Some conclusions can be drawn: the velocity of the air flow and different distributions of coolant flow for turbine blade with multiple cooling air inlets have great influence on the cooling effect; the cooling effect decreases as the temperature ratio decreases; with the same mass cold gas, the less film cooling holes, the worse cooling effect; therefore, a reasonable air flow distribution plays an important role in obtaining good cooling effect.

Background Elevated levels of norepinephrine (NE) have been reported in recipients of small-for-size liver (SFS) grafts in the perioperative period. The aim of the study is to test the hypothesis that although circulating catecholamines are elevated in recipients of SFS grafts, they are not the primary agents responsible for the hepatic artery (HA) vasospasm. Methods Female porcine recipients receiving a 20% ( n = 10) partial liver graft were compared with a control group, using 60% partial liver transplanted grafts ( n = 9). Hepatic blood flow (PVF, HAF) and levels of plasma catecholamines (epinephrine and NE) were measured at designated time points through postoperative day (POD) 7. Phentolamine (PA), an α-adrenergic blocker, was administered at doses of 1 to 112.5 ug/kg/min through an indwelling HA to the recipients of 20% group on POD1 ( n = 5). Results In the 20% group following reperfusion, HA vasospasm was found at 10, 60, and 90 min, and persisted on POD 3 and POD 7. Plasma NE levels increased after reperfusion in 20% and 60% groups and peaked at 6 h with 10- to 13-fold increased levels compared with baseline. In the 20% group, NE levels remained elevated up to POD 7. PA infusion at low (1–10 ug/kg/min) and high (12.5–112.5 ug/kg/min) doses did not reverse the reduced HAF observed in 20% group recipients. Conclusion Elevated serum NE does not appear to be the primary factor mediating HA vasospasm in the porcine SFS graft.

Background Hepatic artery vasoconstriction plays a major role in the pathophysiology of the small-for-size (SFS) liver graft injury and is reversed by adenosine. The A2a adenosine receptor (AR) has been suggested to be one of the key receptors that modulate hepatic hemodynamic changes. The aim of the study is to define the effects of the A2a AR agonist, regadenoson, in modulating hepatic artery flow (HAF) in SFS liver grafts of a porcine model. Methods Seven female recipient pigs (66–70 kg) receiving 20% liver grafts were treated with regadenoson, 0.1 ug/kg/min starting on POD1 (n = 7). Results were compared with those with untreated 20% liver grafts (n= 8). The recipients were observed for 14 d. Hepatic artery flow (HAF) and portal vein flow (PVF) were recorded. Liver biopsies and serum samples were also taken at the designed time points through postoperative day (POD)14. Results Dose-response curves of regadenoson established 0.1 ug/kg/min as the most effective dose of regadenoson for maintaining an increase in HAF. No adverse effects were seen with regadenoson infusion. HAF immediately increased by up to 2.2-fold after regadenoson infusion. The levels of daily average of HAF and percentage of HAF in total liver blood flow were 34.5% and 41.8%, respectively, higher in the regadenoson group than in the untreated group. Histologic scores of hepatic artery spasm and bile duct necrosis were significantly lower in the regadenoson group than in the untreated group (P = 0.01 and 0.04, respectively). The complication rates of hepatic artery thrombosis and gastrointestinal bleeding were lower in the regadenoson group than in the untreated group (0/7, 0% versus 2/8, 25% and 0/7, 0% versus 2/8 and 25%, respectively). The 14-d survival rates were 4/7 (57.1 %) in regadenoson group compared with 2/8 (25%) in the untreated group. Conclusion Adenosine A2a AR agonist, regadenoson, increases HAF in the recipients of SFS grafts with modest improvements in outcome.

The aim of the study is to define the role of the HABR in the pathophysiology of the SFS liver graft and to demonstrate that restoration of hepatic artery flow (HAF) has a significant impact on outcome and improves survival. Nine pigs received partial liver allografts of 60% liver volume, Group 1; 8 animals received 20% LV grafts, Group 2; 9 animals received 20% LV grafts with adenosine infusion, Group 3. HAF and portal vein flow (PVF) were recorded at 10 min, 60 min and 90 min post reperfusion, on POD 3 and POD 7 in Group 1, and daily in Group 2 and 3 up to POD 14. Baseline HAF and PVF (ml/100 g/min) were 29 +/- 12 (mean +/- SD) and 74 +/- 8 respectively, with 28% of total liver blood flow (TLBF) from the HA and 72% from the PV. PVF peaked at 10 mins in all groups, increasing by a factor of 3.8 in the 20% group compared to an increase of 1.9 in the 60% group. By POD 7-14 PVF rates approached baseline values in all groups. The HABR was intact immediately following reperfusion in all groups with a reciprocal decrease in HAF corresponding to the peak PVF at 10 min. However in the 20% group HAF decreased to 12 +/- 8 ml/100 g/min at 90 min and remained low out to POD 7-14 despite restoration of normal PVF rates. Histopathology confirmed evidence of HA vasospasm and its consequences, cholestasis, centrilobular necrosis and biliary ischemia in Group 2. HA infusion of adenosine significantly improved HAF (p < .0001), reversed pathological changes and significantly improved survival (p = .05). An impaired HABR is important in the pathophysiology of the SFSS. Reversal of the vasospasm significantly improves outcome.

We have found differences among the populations of hepatitis C virus sequences in serum, peripheral blood mononuclear cells (PBMCs), and various tissues in patients with chronic hepatitis C. These results are compatible with the existence of independent viral compartments in the infected host. Our results also suggest that PBMCs, and probably various tissues, can selectively adsorb viral subpopulations differing in the E2 region.

Although the hepatitis G virus is unlikely to be a primary hepatotropic virus, its replication sites remain unclear. Using highly strand-specific Tth-based reverse transcriptase PCR we searched for the presence of the viral RNA negative strand in various autopsy tissues in two patients who died of end-stage liver disease. In addition, amplified viral sequences were compared in the 5' untranslated and the putative capsid regions by the single-strand conformation polymorphism (SSCP). Negative strand HGV RNA was detected in bone marrow and spleen from both patients and in lymph node tissue from one. All amplified sequences from a given patient were identical when compared by SSCP and direct sequencing. This lack of difference in the composition of quasispecies recovered from various tissues suggests the presence of a single, common viral compartment in the infected host.

It has been reported that hepatitis B virus (HBV) DNA is present in peripheral blood mononuclear cells (PBMCs), although it is unclear whether it actually replicates there or is adsorbed from serum. HBV DNA sequences from the core promoter and precore regions were amplified from PBMCs and serum taken from 13 patients with hepatitis B infection. Analysis by single strand conformation polymorphism, direct sequencing and cloning revealed identical HBV DNA sequences in both PBMCs and serum from five patients with acute hepatitis and in five out of eight patients with chronic hepatitis. However, in the remaining three chronic hepatitis cases, HBV DNA sequences in both PBMCs and serum were different: two patients harboured HBV DNA sequences from their PBMCs with deletions/insertions in the core promoter region and one patient harboured HBV DNA sequences from their PBMCs with two nucleotide substitutions. These findings point to a possible presence of independent HBV DNA replication in PBMCs.

We studied the outcome of hepatitis C virus (HCV) infection in 14 patients with end-stage HCV-related liver disease who received HCV-positive liver allografts. Viral sequences specific for donor and recipient were established by direct sequencing of PCR products from the NS5 region and by single-strand conformation polymorphism. Within a few months after transplantation the donor strain took over the recipient strain in 8 patients while in 6 patients it was the recipient strain which ultimately prevailed. Donor and recipient were infected by identical genotypes in 6 donor/recipient pairs and by different genotypes in the remaining 8 pairs. Subtype 1b and type 1 (1a + 1b) became the predominant strains in all recipient/donor pairs in which they were present. Patients retaining their own strain were found to have significantly more active liver disease than those infected by the donor strain. We show that HCV superinfection and overtake phenomena occur in humans and suggest that genotypes 1b and 1 (1a + 1b) may possess replicative advantages over other genotypes. Furthermore, we provide evidence of the existence of interference preventing simultaneous continuous infection even by the same genotype strains. The development of active liver disease associated with recipient strain infection and mild or no disease associated with infection from the donor suggests various pathogenic abilities of different HCV strains.

The aim of the study is to define the role of the HABR in the pathophysiology of the SFS liver graft and to demonstrate that restoration of hepatic artery flow (HAF) has a significant impact on outcome and improves survival. Nine pigs received partial liver allografts of 60% liver volume, Group 1; 8 animals received 20% LV grafts, Group 2; 9 animals received 20% LV grafts with adenosine infusion, Group 3. HAF and portal vein flow (PVF) were recorded at 10 min, 60 min and 90 min post reperfusion, on POD 3 and POD 7 in Group 1, and daily in Group 2 and 3 up to POD 14. Baseline HAF and PVF (ml/100 g/min) were 29 +/- 12 (mean +/- SD) and 74 +/- 8 respectively, with 28% of total liver blood flow (TLBF) from the HA and 72% from the PV. PVF peaked at 10 mins in all groups, increasing by a factor of 3.8 in the 20% group compared to an increase of 1.9 in the 60% group. By POD 7-14 PVF rates approached baseline values in all groups. The HABR was intact immediately following reperfusion in all groups with a reciprocal decrease in HAF corresponding to the peak PVF at 10 min. However in the 20% group HAF decreased to 12 +/- 8 ml/100 g/min at 90 min and remained low out to POD 7-14 despite restoration of normal PVF rates. Histopathology confirmed evidence of HA vasospasm and its consequences, cholestasis, centrilobular necrosis and biliary ischemia in Group 2. HA infusion of adenosine significantly improved HAF (p.0001), reversed pathological changes and significantly improved survival (p = .05). An impaired HABR is important in the pathophysiology of the SFSS. Reversal of the vasospasm significantly improves outcome.

Hepatitis B virus (HBV) is the major etiological agent of hepatocellular carcinoma (HCC). Whether any particular viral variants are associated with HCC is unknown. We studied 53 Gambian patients with HCC and 33 HBsAg positive controls. A functional part of HBV core promoter and whole precore region were sequenced directly and/or after cloning. HBV DNA was amplified from sera from 27 HCC patients and in all controls. Fourteen (52%) patients and 12 (36%) controls (NS) were found to harbor an HBV strain with G to A transition mutation at position 1896 leading to HBeAg negative phenotype. Nine (33%) HCC patients and 2 (6%) controls (p < 0.01) harbored a mixture of wild type and HBV strains with deletions/insertions; strong consensus sequences for topoisomerase I breakage were located in the vicinity of these changes. In Africa, HCC is associated with HBV strains that have deletions/insertions in the HBV core promoter region.

Background In this study, we determined the prevalence of hepatitis G virus (HGV) infection in end-stage hepatitis C virus (HCV)-related liver disease and examined the influence of HGV coinfection on the outcome of liver transplantation. Methods HGV was detected by reverse transcriptase-polymerase chain reaction and Southern blotting in sera drawn from 159 patients who were known to be HCV infected before transplantation. Patients were followed up for a mean of 28.4 months after transplantation. Results Forty-one (25.3%) patients were HGV positive and the prevalence of HGV infection was similar for different HCV genotypes. Both HGV-positive and -negative groups had similar survival, recurrence rates, inflammatory activity scores, and degree of fibrosis at the time of recurrence. Conclusion Infection with HGV is common in end-stage HCV-infected patients presenting for liver transplantation. It influences neither the outcome of liver transplantation nor the recurrence of hepatitis in the graft.

Background. Chronic immunosuppressive (IS) therapy impairs normal T-cell immune surveillance and may predispose to opportunistic infections and malignancies that represent life-threatening complication of solid-organ transplantation (SOTx). Our study was designed to ascertain the impact of chronic in vivo administration of IS on the ability of monocyte-derived dendritic cells (MoDC) to differentiate, mature, and function ex vivo. The potential of these cells to be implemented for DC-based adoptive immunotherapy was also considered. Methods. MoDCs were propagated by conventional procedures, their phenotype was analyzed by flow cytometry, and their function was assessed by mixed leukocyte reaction, enzyme-linked immunoadsorbent assay, and ELISPOT assays. Nuclear translocation of nuclear factor (NF)-kB was analyzed by electrophoretic mobility shift assay. Results. Circulating DC1s in peripheral blood were reduced in SOTx patients. MoDCs generated from patients displayed higher endocytic activity versus normal DCs, indicating their comparative immaturity. Patients’ DCs exposed to pro-inflammatory cytokines (tumor necrosis factor-, interleukin [IL]-1, and IL-6) were less able to mature, to stimulate recall antigen (Ag)- or allo–Ag-induced proliferation responses, or to secrete IL-12p70. These deficiencies were associated with a decrease in NF-kB translocation. In contrast, combination of pro-inflammatory cytokines and interferon (IFN)- (a Th1-polarizing factor) augmented patients’ DC1-type function and IL-12p70 production by way of an NF– kB-independent mechanism. Conclusions. Chronic IS restrains DC differentiation, maturation, and function at a transcriptional level; however, type-1 polarizing potential of patients’ DC1 can be augmented ex vivo by a two-signal stimulation provided by pro-inflammatory cytokines and IFN-. These results may have implications for DC-based immunotherapy of malignancies in the transplantation setting.

Hepatitis C virus (HCV)-related cirrhosis is the leading indication for orthotopic liver transplantation (OLTx). HCV recurrence is universal after OLTx, with a highly variable course. This study aimed to find factors that affect progression of fibrosis in recurrent HCV.Fifty-eight HCV patients underwent OLTx at our center who were selected on the basis of available preOLTx serum or explanted liver sample and liver biopsy obtained at least 6 months postOLTx. All liver biopsies were performed when clinically indicated and were scored using the modified Hepatitis Activity Index (HAI). Primary immunosuppression consisted of tacrolimus and prednisone.The group included 41 males (mean age 49.6 years). HCV genotype distribution was 1a, 31 (53%); 1b, 16 (28%), and others 11 (19%). The mean follow-up was 53.1 months. Patients with genotype 1a (n=31; mean 46.3 months) had significantly lower fibrosis-free survival analyzed by the presence of fibrosis stages 5 and 6 when compared with other genotypes (n=27; mean 60.1 months; P=0.0088, log rank test). Mean HAI scores were significantly higher in HCV genotype 1a, although there were no differences in survival between genotypes. Similarly, patients with cytomegalovirus (CMV) infection postOLTx (n=4) had a higher fibrosis progression rate compared with those without CMV (n=54) (mean fibrosis-free survival 29.0 vs. 53.0 months P=0.0004, log-rank test). Human leukocyte antigen matching and rate of acute rejection did not influence progression of fibrosis.Patients with HCV genotype 1a and those developing CMV postOLTx have a higher rate of hepatic fibrosis progression after OLTx for HCV-related chronic liver disease.

Background. We have previously studied hepatitis C (HCV)-infected recipients of livers from HCV-infected donors and found that either the donor’s strain or the recipient’s strain predominate in serum. The current study was undertaken to determine whether these changes are complete and whether they are reflected in the population of virus associated with peripheral blood mononuclear cells (PBMCs). Methods. We analyzed HCV ribonucleic acid from sequential serum and PBMC samples from 11 and 8 patients, respectively. The relatively stable NS5 region was chosen for analysis because it allowed for dependable identification of donor and recipient strains. Viral sequences were analyzed by direct sequencing and by sensitive strain–specific polymerase chain reaction assays. These assays were capable of detecting the minor sequence present at a concentration 1:104–10−7 below that of the major sequence. Results. Five patients retained their original infecting strain; the donor strain was detected only transiently. In the remaining six patients, recipient strain was detected for the first few weeks, after which only the donor strain was consistently present. However, in one patient the second nondominant strain was detected from the background of the major strain on a single occasion 8 months after transplantation. All changes in serum were closely paralleled by those occurring in PBMCs. Conclusions. Viral population changes in the setting of liver transplantation from HCV-infected donors to HCV-infected recipients occur simultaneously in PBMCs and serum. The takeover of one strain by another in PBMC- and serum-derived viral populations seemed to be complete and long lasting.

It is unclear whether the sequence populations of hepatitis C virus (HCV) quasispecies in the liver and in serum are different, as a variety of studies on this subject provide conflicting results. In the current study, the populations of HCV 5' untranslated region (5' UTR) sequences in paired serum and liver samples from six patients with chronic hepatitis were analysed. Liver-derived, negative-strand viral RNA was amplified with a highly strand-specific Tth-based assay, and extensive measures, including accounting for template copy number, were undertaken to lower the risk of sporadic artefactual polymorphism. Amplified sequences were compared by single-strand conformation polymorphism analysis and by direct sequencing of identified differences. In four patients, liver samples were found to contain variants within the quasispecies which were not found in serum or negative-strand viral RNA, while in the remaining two patients, low virus titre prevented a reliable quasispecies analysis. These results suggest the presence in the same individual of HCV variants differing in the 5' UTR and possibly replicating with different kinetics.

Background. In hepatitis C virus (HCV)-positive patients receiving HCV-positive liver allografts either the donor or recipient strain overtakes the other strain. Whether these changes are reflected in peripheral blood mononuclear cell (PBMC)-associated virus is unknown. Methods. We analyzed by single-strand conformation polymorphism and sequencing HCV RNA from serum and PBMCs from a liver transplant recipient whose indigenous strain was replaced by the donor strain. Results. Only the recipient strain was detectable in serum and PBMCs 3 and 5 days after transplantation; at day 7 and 8, a mixture of both was present in the PBMCs, but only recipient strain was detectable in serum. This coincided with the peak presence of donor DNA in recipient PBMCs. From day 14 on, HCV sequences in serum and PBMCs were indistinguishable. Conclusions. Overtake phenomenon in the setting of liver transplantation from infected donors to infected recipients is manifested in PBMCs. Cells released from infected graft carry donor HCV strain.

A PCR-based technique was used to detect hepatitis B virus (HBV) integration in peripheral blood mononuclear cells from patients with chronic hepatitis B. Integrated HBV DNA sequences, with virus-cell junctions located in the cohesive region between direct repeat 1 (DR1) and DR2, were found in 2 of 10 studied patients.

The existence of extrahepatic replication sites of hepatitis C virus (HCV) remains controversial. Highly strand-specific Tth-based reverse transcriptase-polymerase chain reaction was used to search for the presence of viral RNA negative strand in lymph nodes from 16 patients with AIDS and in peripheral blood mononuclear cells (PBMC) from 14 other human immunodeficiency virus (HIV)-positive patients. Negative-strand HCV RNA was detected in lymph node samples from 10 patients (63%) and in PBMC from 5 (36%). This suggests that, at least under circumstances of impaired immunity associated with HIV infection, HCV is lymphotropic in vivo. However, the clinical implications of these findings need to be further investigated.

The ‘long PCR’ was used for amplification of hepatitis C virus (HCV) subgenomic fragments from liver. After testing several commercially available systems, it was found that Tth as the major enzyme is superior to using Taq. Employing a mixture of Tth and Vent polymerase (rTth polymerase, XL, Perkin Elmer) it was possible to amplify 4.6-kb and 9-kb fragments from biological samples containing as little as 10 2 and 10 4 viral copies, respectively. It was also demonstrated that ‘long PCR’ is useful for joining together large size amplification products.

The replication sites of the recently discovered hepatitis G virus (HGV) remain unknown. Using highly strand-specific Tth-based reverse transcriptase PCR, we searched for the presence of viral RNA negative strand in multiple autopsy tissues from four patients with AIDS and in peripheral blood mononuclear cells from six other human immunodeficiency virus-positive patients. Negative-strand HGV RNA was detected in three of four bone marrow samples, in two of two spleen samples, and in one of four liver tissue samples. However, the specific cellular site of replication within the positive tissues was not determined. This study does not support HGV as a primary hepatotropic virus.

Peripheral blood mononuclear cells (PBMCs) from 27 hepatitis C virus (HCV)-infected patients were analysed for the presence of HCV negative strand RNA with strand-specific Tth-based RT-PCR. No negative strand RNA was detected in any sample, and positive strand HCV sequences amplified from PBMCs were identical to those found in serum. These findings suggest that HCV does not replicate in PBMCs, and the presence of HCV sequences at this site is compatible with passive virus adsorption and/or contamination by circulating virus.