Analysis of N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine/N1‐acetyl‐5‐methoxy‐kynuramine formation from melatonin in mice

Abstract: The interactions of melatonin, a potent endogenous antioxidant, with reactive oxygen species generate several products that include N¹‐acetyl‐N²‐formyl‐5‐methoxykynuramine (AFMK) and N¹‐acetyl‐5‐methoxy‐kynuramine (AMK). The physiological or pathological significance of AFMK/AMK formation during the process of melatonin metabolism in mammals has not been clarified. Using a metabolomic approach in the current study, the AFMK/AMK pathway was thoroughly investigated both in mice and humans. Unexpectedly, AFMK and AMK were not identified in the urine of humans nor in the urine, feces or tissues (including liver, brain, and eyes) in mice under the current experimental conditions. Metabolomic analysis did identify novel metabolites of AMK, i.e. hydroxy‐AMK and glucuronide‐conjugated hydroxy‐AMK. These two newly identified metabolites were, however, not found in the urine of humans. In addition, oxidative stress induced by acetaminophen in the mouse model did not boost AFMK/AMK formation. These data suggest that AFMK/AMK formation is not a significant pathway of melatonin disposition in mice, even under conditions of oxidative stress.     

Considerations of a One‐and‐One‐Half Ventricle Repair in a 47‐Year‐Old Patient

This report describes the management of a 47‐year‐old patient with Ebstein's anomaly and severe right ventricular dysfunction. Her complicated postoperative course is discussed. In addition, age‐related differences in the hemodynamic response to a one‐and‐one‐half ventricle repair are reviewed.     

Effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone on carbon tetrachloride‐induced hepatic cirrhosis in rats

Aim: The present study was undertaken to evaluate the effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone (HTHQ), a synthesized vitamin E derivative, on carbon tetrachloride (CCl₄)‐induced cirrhosis. Methods: Rats were treated with hypodermic injections of CCl₄ twice a week to induce the hepatic cirrhosis, and given drinking water containing HTHQ or solvent. Primary cultures of rat hepatocytes were performed to evaluate the effects of HTHQ on the expression of inducible nitric oxide synthase (iNOS). Results: Masson's staining of rat livers showed fibrosis around pseudo‐lobules in the CCl₄ group, the lesions being reduced in the CCl₄ HTHQ group. Increases in liver tissue hydroxyproline and α₁(I) collagen, α‐smooth muscle actin and iNOS induced by CCl₄, were also markedly diminished by HTHQ. Furthermore, both HTHQ and vitamin E attenuated interleukin‐1β‐induced iNOS protein expression in cultured hepatocytes, the potency of HTHQ being 10‐times higher than that of vitamin E. Conclusion: HTHQ may inhibit development of hepatic cirrhosis in rats, more potently than vitamin E, by inhibiting the iNOS expression in hepatocytes. Because vitamin E has a radical scavenging action, roles of NO and peroxynitrite will be discussed in the effects of HTHQ on the fibrosis.     

Efficacy of short‐term dexamethasone therapy in acute‐on‐chronic pre‐liver failure

Aim: Acute‐on‐chronic pre‐liver failure (pre‐ACLF) is defined as a severe acute episode of chronic hepatitis B characterized by serum bilirubin of 171 µmol/L or more, alanine aminotransferase of five times or more the upper limit of normal and prothrombin activity of more than 40%, having a potential for progression to acute‐on‐chronic liver failure (ACLF). This study is to evaluate the efficacy of short‐term dexamethasone in pre‐ACLF. Methods: One hundred and seventy patients were assigned to dexamethasone therapy and control group at a ratio of 1:2. For the two groups, we compared biochemical indicators, the incidence of ACLF and mortality. The influential factors on the mortality of patients with pre‐ACLF were studied by Cox proportional hazards models. Results: The significantly lower incidence of ACLF and higher survival rate were observed in patients on dexamethasone therapy (8.9%, 96.4%, respectively) than in control patients (70.2%, 52.6%, respectively; P < 0.001). Dexamethasone treatment was an independent factor influencing the survival rate (P < 0.001, odds ratio = 0.055, 95% confidence interval = 0.013–0.225). During 4 weeks of treatment, serum bilirubin levels of survival patients were significantly lower in the dexamethasone group than control group. Conclusion: Five‐day dexamethasone therapy is effective in improving the liver function and survival rate of patients with pre‐ACLF.     

Over‐expression of Toll‐like receptors and their ligands in small‐for‐size graft

Aim: Toll‐like receptors (TLRs) participate in several physiological and pathological processes of transplantation, including inflammation and allograft rejection, but the expression of TLRs and their ligands remains undetermined in small‐for‐size graft transplantation. Methods: A non‐arterialized partial liver transplantation model was used. The expression of TLR2 and TLR4 mRNA and protein, CD14 and Myeloid Differentiation‐2 (MD‐2) mRNA, as well as TLR2 and TLR4 exogenous ligands (endotoxin) and endogenous ligands [heat shock protein (HSP) 60 and 70] were assessed. The signaling pathways induced by TLR2 and TLR4 were also assessed. Results: In small‐for‐size liver graft, the expression of mRNA and protein of TLR2 and TLR4, CD14 and MD‐2 mRNA, as well as endogenous ligands of TLR2 and TLR4 such as HSP60 and HSP70 was quickly and significantly increased after reperfusion, and reached a peak at 3 h after reperfusion. The levels of exogenous ligands (endotoxin) were increased and reached a peak at 6 h after reperfusion. The appearance of TLR2 and TLR4 mRNA was accompanied by increased HSP 60 and 70 mRNA within 24 h after reperfusion. In the small‐for‐size group, the peak levels of TLRs and their endogenous ligands appeared earlier than those in the full size group; the peak levels of TLRs and their endogenous and exogenous ligands were higher than those in the full size group. Conclusion: TLR2 and TLR4, as well as their endogenous and exogenous ligands were activated in small‐for‐size liver graft transplantation.     

Five‐year clinical outcomes of sirolimus‐eluting versus paclitaxel‐eluting stents in high‐risk patients

Objectives and Background : First generation drug‐eluting stents have shown differential efficacy in high‐risk patient subsets at one year. It is unclear whether these differences endure over the medium‐ to long‐term. We compared the five‐year clinical efficacy and safety of sirolimus‐eluting stents (SES) and paclitaxel‐eluting stents (PES) in a population of high‐risk patients. Methods : The patient cohorts of the ISAR‐DESIRE, ISAR‐DIABETES, and ISAR‐SMART‐3 randomized trials were followed up for five years and data were pooled. The primary efficacy endpoint of the analysis was the need for target lesion revascularization (TLR) during a five‐year follow‐up period. The primary safety endpoint was the combination of death or myocardial infarction (MI) after five years. Results : A total of 810 patients (405 patients in the SES group and 405 patients in the PES group) was included. Over five years TLR was reduced by 39% with SES compared with PES stent (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.44–0.85; P = 0.004). No difference was observed according to death or MI rates between the two groups (HR 1.10; 95% CI 0.80–1.50; P = 0.57). Definite stent thrombosis occurred in 0.2% (n = 1) in the SES group and in 1.6% (n = 6) in the PES group (HR 0.16; 95% CI 0.02–1.34; P = 0.12). Conclusions : In high‐risk patient subsets the lower rate of 12‐month TLR observed with SES in comparison PES is maintained out to five years. In terms of safety, although there was no difference in the overall incidence of death or MI, there was a trend towards more frequent stent thromboses with PES. © 2011 Wiley‐Liss, Inc.     

Periplogenin‐3‐O‐ ‐D‐Glucopyranosyl ‐(1→6)‐ ‐D‐Glucopyaranosyl‐ ‐(1→4) ‐D‐Cymaropyranoside,Isolated from Aegle marmelos Protects Doxorubicin Induced Cardiovascular Problems and Hepatotoxicity in Rats

Doxorubicin is a common chemotherapeutic anticancer drug. Its use is associated with adverse effects including cardiotoxicity. Several therapeutics interventions have been attempted to reduce the toxicity and to improve the efficacy of the drug. However, on phytochemicals very few investigations have been made. In the present study we have evaluated the potential of a cardenolide, periplogenin, isolated from the leaves of Aegle marmelos in protecting the doxorubicin induced cardiotoxicity and lipid peroxidation (LPO) in rats. Doxorubicin induced cardiac and hepatotoxicity were characterized by marked biochemical changes including an increase in serum creatine kinase–MB (CK–MB), glutamate‐pyruvate transaminase (SGPT), and tissue LPO, with a decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). It also increased the levels of different serum lipids, but decreased the amount of high‐density lipoprotein (HDL). Cotherapy of the test cardenolide and doxorubicin for 4 weeks reversed all these adverse effects. However, out of three different concentrations (12.5, 25, and 50 mg/kg p.o.) of the test periplogenin, 25 mg/kg appeared to be most effective. When its efficacy was compared with that of vitamin E (α‐tocopherol) the isolated compound exhibited a better therapeutic potential. The isolated periplogenin from the leaves of A. marmelos could potentially inhibit doxorubicin‐induced cardiovascular problems in rats. However, its moderate dose was found to be most effective.     

Prognostic value of complete remission status at end‐of‐treatment FDG‐PET in R‐CHOP‐treated diffuse large B‐cell lymphoma: systematic review and meta‐analysis

This study systematically reviewed and meta‐analysed the prognostic value of complete remission status at end‐of‐treatment ¹⁸F‐fluoro‐2‐deoxy‐d ‐glucose positron emission tomography (FDG‐PET) in diffuse large B‐cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP). The systematic PubMed/MEDLINE search yielded seven suitable studies comprising a total of 737 R‐CHOP‐treated DLBCL patients who were in complete remission at end‐of‐treatment FDG‐PET. Overall, the methodological quality of included studies was reasonable. The disease relapse rate among all patients with complete remission status according to end‐of‐treatment FDG‐PET ranged from 7·0% to 20·0%, with a weighted summary proportion of 13·7%. Five of seven studies reported progression‐free survival (PFS) of these patients at various specific time points, i.e., 2‐year PFS (n = 1), estimated 3‐year PFS (n = 3) and 5‐year PFS (n = 1), which was 83%, 85–86·4% and 75%, respectively. Three of seven studies reported overall survival (OS) of these patients at various specific time points, i.e., estimated 3‐year OS (n = 2) and estimated 5‐year OS (n = 1), which were 90%, 93·6% and 83%, respectively. In conclusion, a non‐negligible proportion of R‐CHOP‐treated DLBCL patients who achieve complete remission according to end‐of‐treatment FDG‐PET experiences disease relapse during follow‐up.     

The anti‐lymphoma activity of antiviral therapy in HCV‐associated B‐cell non‐Hodgkin lymphomas: a meta‐analysis

Many epidemiological studies provide solid evidence for an association of chronic hepatitis C virus (HCV) infection with B‐cell non‐Hodgkin's lymphoma (B‐NHL). However, the most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B‐NHL regression after HCV eradication by antiviral therapy (AVT). We conducted a literature search to identify studies that included patients with HCV‐associated B‐NHL (HCV‐NHL) who received AVT, with the intention to treat lymphoma and viral disease at the same time. The primary end point was the correlation of sustained virological response (SVR) under AVT with lymphoma response. Secondary end points were overall lymphoma response rates and HCV‐NHL response in correlation with lymphoma subtypes. We included 20 studies that evaluated the efficacy of AVT in HCV‐NHL (n = 254 patients). Overall lymphoma response rate through AVT was 73% [95%>confidence interval, (CI) 67–78%]. Throughout studies there was a strong association between SVR and lymphoma response (83% response rate, 95%>CI, 76–88%) compared to a failure in achieving SVR (53% response rate, 95%>CI, 39–67%, P = 0.0002). There was a trend towards favourable response for AVT in HCV‐associated marginal zone lymphomas (response rate 81%, 95%>CI, 74–87%) compared to nonmarginal zone origin (response rate 71%, 95%>CI, 61–79%, P = 0.07). In conclusion, in the current meta‐analysis, the overall response rate of HCV‐NHL under AVT justifies the recommendation for AVT as first‐line treatment in patients who do not need immediate conventional treatment. The strong correlation of SVR and lymphoma regression supports the hypothesis of a causal relationship of HCV and lymphomagenesis.