Heme breakdown and ischemia/reperfusion injury in grafted liver during living donor liver transplantation

Living donor liver transplantation (LDLT) requires ischemia/reperfusion (I/R), which can cause early graft injury. However, the detailed mechanism of I/R injury remains unknown. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme catabolism and results in the production of iron, carbon monoxide (CO), and biliverdin IXα. Furthermore, in animals, HO-1 has a protective effect against oxidative stress associated with I/R injury. However, in humans, the molecular mechanism and clinical significance of HO-1 remain unclear. We previously demonstrated that exhaled CO levels increase during LDLT, and postulated that this may indicate I/R injury. In this study, we elucidate the origin of increased exhaled CO levels and the role of HO-1 in I/R injury during LDLT. We studied 29 LDLT donors and recipients each. For investigation of HO-1 gene expression by polymerase chain reaction and HO-1 localization by immunohistological staining, liver biopsies from the grafted liver were conducted twice, once before and once after I/R. Exhaled CO levels and HO-1 gene expression levels significantly increased after I/R. In addition, HO-1 levels significantly increased after I/R in Kupffer cells. Furthermore, we found a significant positive correlation between exhaled CO levels and HO-1 gene expression levels. These results indicated that increased heme breakdown in the grafted liver is the source of increased exhaled CO levels. We also found a significant relationship between HO-1 gene expression levels and alanine aminotransferase (ALT) levels; i.e., the higher the HO-1 gene expression levels, the higher the ALT levels. These results suggest that HO-1-mediated heme breakdown is caused by I/R during LDLT, since it is associated with increased exhaled CO levels and liver damage

Heme Oxygenase-1 is an Essential Cytoprotective Component in Oxidative Tissue Injury Induced by Hemorrhagic Shock

Hemorrhagic shock causes oxidative stress that leads to tissue injuries in various organs including the lung, liver, kidney and intestine. Excess amounts of free heme released from destabilized hemoproteins under oxidative conditions might constitute a major threat because it can catalyze the formation of reactive oxygen species. Cells counteract this by rapidly inducing the rate-limiting enzyme in heme breakdown, heme oxygenase-1 (HO-1), which is a low-molecular-weight stress protein. The enzymatic HO-1 reaction removes heme. As such, endogenous HO-1 induction by hemorrhagic shock protects tissues from further degeneration by oxidant stimuli. In addition, prior pharmacological induction of HO-1 ameliorates oxidative tissue injuries induced by hemorrhagic shock. In contrast, the deletion of HO-1 expression, or the chemical inhibition of increased HO activity ablated the beneficial effect of HO-1 induction, and exacerbates tissue damage. Thus, HO-1 constitutes an essential cytoprotective component in hemorrhagic shock-induced oxidative tissue injures. This article reviews recent advances in understanding of the essential role of HO-1 in experimental models of hemorrhagic shock-induced oxidative tissue injuries with emphasis on the role of its induction in tissue defense

Induction of metallothionein synthesis in cultured cells by substances released from endotoxin-activated macrophages.

The involvement of macrophages in the induction of metallothionein (MT) synthesis by bacterial endotoxin was studied in vitro. Rat peritoneal macrophages were incubated with endotoxin. The incubation medium from endotoxin-activated macrophages accelerated MT synthesis by human hepatic Chang cells. However, the incubation medium from non-activated macrophages did not. Endotoxin added to the culture medium of Chang cells was ineffective in inducing MT synthesis. The contents of zinc, copper and cadmium, which are primary inducers of MT, in the incubation medium of macrophages in the presence of endotoxin were not different from those in the absence of endotoxin. These results suggest that MT synthesis is induced by endotoxin-treated macrophages.</p

Effectiveness, safety, and factors associated with the clinical success of endoscopic biliary drainage for patients with hepatocellular carcinoma: a retrospective multicenter study

Background Only a few reports have assessed the effectiveness of endoscopic biliary drainage (EBD) in hepatocellular carcinoma (HCC) patients with obstructive jaundice and liver dysfunction. Methods This was a retrospective study based on the clinical databases from the Okayama University Hospital and 10 affiliated hospitals. All patients received EBD for jaundice or liver dysfunction. The indication for EBD was aggravation of jaundice or liver dysfunction with intrahepatic bile duct (IHBD) dilation. The technical and clinical success rate, complications, factors associated with clinical failure, and survival duration were evaluated. Results A total of 107 patients were enrolled in this study. Technical success was achieved in 105 of 107 patients (98.1%). Clinical success was achieved in 85 of 105 patients (81%). Complications related to endoscopic retrograde cholangiography (ERC) occurred in 3 (2.8%) patients. Child–Pugh class C (odds ratio 3.90, 95% confidence interval [CI] 1.47–10.4, p = 0.0046) was the only factor associated with clinical failure, irrespective of successful drainage. The median survival duration was significantly longer in patients with clinical success than in those without clinical success (5.0 months vs. 0.93 months; hazard ratio [HR] 3.2, 95% CI 1.87–5.37). HCC Stage I/II/III (HR 0.57, CI 0.34–0.95, p = 0.032), absence of portal thrombosis (HR 0.52, CI 0.32–0.85, p = 0.0099), and clinical success (HR 0.39, CI 0.21–0.70, p = 0.0018) were significant factors associated with a long survival. Conclusions EBD for obstructive jaundice and liver dysfunction in patients with HCC can be performed safely with a high technical success rate. Clinical success can improve the survival duration, even in patients expected to have a poor prognosis

Effects of oral morphine for pain relief of peripheral arterial disease

Peripheral arterial disease often causes ischemic ulcers due to impaired blood flow and consequentially induces intractable pain. For these patients, we have recently begun to administer morphine orally. In this study, we retrospectively examined the effects of oral morphine for the relief of pain caused by peripheral arterial disease. Oral morphine was administered to 17 cases of peripheral arterial disease between January, 2004 and February, 2006. The initial dosage was 5 mg or 10 mg, started on an as-needed basis. After the daily dosage of morphine became constant, we divided the dosage into four or six times a day and administered it regularly. With the exception of one case, a small amount of oral morphine, from 20 mg to 70 mg a day, could alleviate patient's pain. Eight cases had side effects such as nausea, constipation or drowsiness. Oral morphine is effective for pain relief of peripheral arterial disease patients. However, now in Japan, oral morphine, which we can prescribe for those patients with insurance, has a shorter duration of action, so we need to administer slow-release morphine. Oral morphine must be administered carefully because many peripheral arterial disease patients have cardiac disease or renal dysfunction as complications

Nonimmersive Virtual Reality Mirror Visual Feedback Therapy and Its Application for the Treatment of Complex Regional Pain Syndrome: An Open-Label Pilot Studyp me_819 622..629

Abstract Objective. Chronic pain conditions such as phantom limb pain and complex regional pain syndrome are difficult to treat, and traditional pharmacological treatment and invasive neural block are not always effective. Plasticity in the central nervous system occurs in these conditions and may be associated with pain. Mirror visual feedback therapy aims to restore normal cortical organization and is applied in the treatment of chronic pain conditions. However, not all patients benefit from this treatment. Virtual reality technology is increasingly attracting attention for medical application, including as an analgesic modality. An advanced mirror visual feedback system with virtual reality technology may have increased analgesic efficacy and benefit a wider patient population. In this preliminary work, we developed a virtual reality mirror visual feedback system and applied it to the treatment of complex regional pain syndrome. Design. A small open-label case series. Five patients with complex regional pain syndrome received virtual reality mirror visual feedback therapy once a week for five to eight sessions on an outpatient basis. Patients were monitored for continued medication use and pain intensity. Results. Four of the five patients showed &gt;50% reduction in pain intensity. Two of these patients ended their visits to our pain clinic after five sessions. Conclusion. Our results indicate that virtual reality mirror visual feedback therapy is a promising alternative treatment for complex regional pain syndrome. Further studies are necessary before concluding that analgesia provided from virtual reality mirror visual feedback therapy is the result of reversing maladaptive changes in pain perception

Zinc metabolism in the endotoxin-treated rats

The effect of endotoxin administration on zinc metabolism was studied in rats. In the endotoxin-treated rats, serum zinc concentration was significantly reduced as compared to saline-treated rats (control group). On the other hand, hepatic zinc concentration was significantly increased after endotoxin administration as compared to the control group. However, the zinc concentrations of the liver cell components showed slightly dissimilarity. In the mitochondria and cytsol, the concentration increased significantly after endotoxin administration as compared to the control group, whereas no change was observed in the microsomes. Furthermore, we have examined whether the increase of the zinc level in the cytosol of the liver is associated with zinc-binding protein metallothioneins (MTs) or not. MTs also increased significantly after endotoxin administration. Furthermore hepatic MTs were analyzed for MT isoforms. In the endotoxin-treated MT-II was the major Iso-MT. Judging from these results and some other published reports, the role of zinc metabolism in endotoxemia is proposed to be as follows. In endotoxemia the serum zinc concentration is reduced and as a result the production of superoxide by polymorphonuclear leukocytes is increased as zinc has an inhibitory effect on it. This free radical helps the host against the organism. On the other hand zinc accumulation in the liver following endotoxin administration increases the activity of the zinc binding-enzyme and also stabilizes the plasma membrane. MTs induced by endotoxin protect the host from the harmful effects of the free radical in the host by its scavenging action