Effects of branched-chain amino acids-enriched nutrient support for patients undergoing liver resection for hepatocellular carcinoma

Background and Aims: Most patients with hepatocellular carcinoma (HCC) have underlying liver cirrhosis that is frequently associated with a state of protein energy malnutrition. The aim of this study was to evaluate the clinical benefit of perioperative supplementation of a branched‐chain amino acid–enriched nutrient‐mixture for patients undergoing liver resection for HCC. Methods: A total of 112 patients with HCC who underwent hepatic resection were enrolled in this study. These patients were divided into two groups: 40 patients received perioperative supplementation of branched‐chain amino acid–enriched nutrient‐mixture (AEN group) and 72 patients did not (control group). Laboratory data, postoperative complications, duration of hospitalization, and survival were assessed for each group and compared. Results: The overall incidence of postoperative complications was lower in the AEN group (17.5%) than in the control group (44.4%) (P = 0.01). Among the postoperative complications, surgical site infection and bile leakage was observed in 5% of patients in the AEN group and in 15.3% and 12.5% of patients in the control group, respectively. Ascites appeared after the surgery in 7.5% of patients in the AEN group and in 16.7% of patients in the control group. The duration of hospitalization was significantly shorter in the AEN group was than in the control group (P < 0.05). Conclusions: This study strongly suggests that perioperative supplementation of a branched‐chain amino acid–enriched nutrient‐mixture is clinically beneficial in reducing the morbidity associated with postoperative complications and in shortening the duration of hospitalization of patients with chronic liver disease who undergo liver resection for HCC.     

Discovery of immunostimulatory CpG-DNA and its application to tuberculosis vaccine development

DNA containing an unmethylated CpG motif has a potent immunostimulatory effect on the vertebrate immune system. Because such CpG motifs are relatively common in bacterial DNA, but rare in mammalian animal and plant DNA, they may be an evolutionary adaptation augmenting innate immunity, most likely in response to pathogens that replicate within the host cells, such as viruses and intracellular bacteria. Microbial infection induces innate immunity by triggering pattern-recognition systems. The infected cells produce proinflammatory cytokines that directly combat microbial invaders and express costimulating surface molecules, which develop adaptive immunity by inducing distinct T cell differentiation. Bacterial DNA with unmethylated CpG-DNA stimulates vertebrate immature immune cells to induce maturation and to produce TNF-alpha as well as Th1-type cytokines, IL-12 and IFN-gamma. Therefore, CpG-DNA functions as an adjuvant for regulating the initiation of Th1 differentiation. The roles of immunostimulatory CpG motifs in DNA vaccine developments and in therapeutic applications have been discussed.     

Scrotal Ulcers Arising during Treatment with All-trans Retinoic Acid for Acute Promyelocytic Leukemia

All-trans retinoic acid (ATRA) is effective in approximately 90% of the cases of acute promyelocytic leukemia (APL) with a low incidence of adverse effects. We report a patient with APL who developed skin ulcers of the scrotum concomitant with high fever during treatment that included ATRA. Severe fever was promptly alleviated with discontinuation of ATRA, while the ulcers improved gradually over 3 months. As the clinical features are similar to those of Sweet's syndrome, we should be aware of the possibility that this rare adverse effect may occur in the treatment with ATRA.     

Fibrate for treatment of primary biliary cirrhosis

Recent studies of the effectiveness of ursodeoxycholic acid (UDCA) therapy in patients with primary biliary cirrhosis (PBC) reported that UDCA therapy did not necessarily stop the progression of liver fibrosis in all patients, even those with early stage PBC. Thus, there is a need for more effective treatments that could prevent asymptomatic PBC from progressing to the icteric stage. Bezafibrate is effective in approximately two-thirds of non-icteric patients who have not shown a complete response to UDCA. Serum bilirubin, aspartate aminotransferase and γ-guanosine 5'-triphosphate levelswere significantly lower in patients who responded to additional bezafibrate on univariate analysis. The putative mechanism by which bezafibrate acts in cholestasis is by increasing phospholipid output into bile, which forms micelles with the hydrophobic bile acid that reduces its toxicity.     

The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population

BACKGROUND/AIMS: The genetic predisposition on the development of nonalcoholic steatohepatitis (NASH) has been poorly understood. A functional polymorphism Val175Met was reported in phosphatidylethanolamine N-methyltransferase (PEMT) that catalyzes the conversion of phosphatidylethanolamine to phosphatidylcholine. The aim of this study was to investigate whether the carriers of Val175Met variant impaired in PEMT activity are more susceptible to NASH. METHODS: Blood samples of 107 patients with biopsy-proven NASH and of 150 healthy volunteers were analyzed by the polymerase chain reaction (PCR) and restriction fragment length polymorphism. RESULTS: Val175Met variant allele of the PEMT gene was significantly more frequent in NASH patients than in healthy volunteers (p<0.001), and carriers of Val175Met variant were significantly more frequent in NASH patients than in healthy volunteers (p<0.01). Among NASH patients, body mass index was significantly lower (p<0.05), and non-obese patients were significantly more frequent (p<0.001) in carriers of Val175Met variant than in homozygotes of wild type PEMT. CONCLUSIONS: Val175Met variant of PEMT could be a candidate molecule that determines the susceptibility to NASH, because it is more frequently observed in NASH patients and non-obese persons with Val175Met variant of PEMT are facilitated to develop NASH.     

Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is now the most frequent cause of chronic liver impairment in developed countries and is a suggested causative factor in the development of cryptogenic cirrhosis and hepatocellular carcinoma. At present there is no effective and accepted therapy for NASH. The renin-angiotensin system is involved in hepatic fibrosis through activation of hepatic stellate cells, major fibrogenic cells in the liver. Hepatic stellate cells are activated by liver injury to express excessive matrix proteins and profibrogenic cytokines such as transforming growth factor-beta 1. Medicines that inhibit this pathway may be of therapeutic potential in NASH. Using a methionine-choline-deficient rat model of NASH, we studied the potential utility of an angiotensin II type 1 receptor blocker (ARB), olmesartan, on biochemical, histologic, and antioxidant measures of disease activity. ARB significantly attenuated increases in aspartate aminotransferase, activation of hepatic stellate cells, oxidative stress, expression of transforming growth factor-beta 1, expression of collagen genes, and liver fibrosis. CONCLUSION: Our observations strongly suggest a potential preventive role for ARB in the progression of nonalcoholic steatohepatitis.     

CD13/aminopeptidase N in collagen vascular diseases

To determine the significance of CD13/aminopeptidase N in collagen vascular diseases (CVD), we examined its activity and expression in sera and disease sites of patients with CVD. Significantly higher aminopeptidase activity was detected in bronchoalveolar lavage fluid from patients with interstitial lung diseases due to rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM), systemic sclerosis (SSc), and Sjögren's syndrome than from control subjects. Increased aminopeptidase activity and increased expression of CD13/aminopeptidase N protein were found in alveolar macrophages from CVD patients with interstitial lung diseases. Significantly higher aminopeptidase activity was detected in pleural effusions from patients with systemic lupus erythematosus (SLE) than in transudate effusions. The mean aminopeptidase activity in synovial fluids from RA patients was significantly higher than from patients with osteoarthritis. The mean value of serum aminopeptidase activity was significantly higher in patients with SLE, RA, SSc, and PM/DM than in normal subjects. This study suggests that the activity of CD13/aminopeptidase N, locally produced in the disease site, is a useful marker for CVD and that CD13/aminopeptidase N may have an important role in the pathogenesis of CVD.     

Analysis of K-<Emphasis Type="Italic">ras</Emphasis> Codon 12 Mutation in Flat and Nodular Variants of Serrated Adenoma in the Colon

PURPOSE: The developmental process of serrated adenomas is obscure, and the importance of genetic alterations has not been elucidated clearly. The possibility that the developmental process and genetic alterations of serrated adenomas could differ from those of ordinary tubular adenomas was explored in this work. METHODS: Serrated adenomas were obtained by endoscopic resection (n = 57) and divided into two groups: flat (n = 10) and nodular (n = 47). Mutation of the K-ras gene was analyzed by enriched polymerase chain reaction–enzyme-linked mini-sequence assay, which can detect not only the presence of a mutation but also the mutation type of K-ras codon 12 with high sensitivity. Methylation-specific polymerase chain reaction was performed with specific primers for the DNA repair gene O6-methylguanine-DNA methyltransferase. RESULTS: Serrated adenomas located in the rectum were more likely to have a K-ras mutation (9/12, 75 percent), whereas serrated adenomas of the flat type were less likely to have one (1/10, 10 percent). Furthermore, nodular serrated adenomas that occurred in the rectum possessed a high frequency of K-ras gene codon 12 point mutation (8/10, 80 percent) despite an overall frequency of 46.8 percent (22/47). A mutation of the K-ras codon 12 gene was detected in 23 (40.4 percent) of 57 serrated adenomas. Three types of point mutations of codon 12 were detected, with the mutation of GAT being observed most frequently. CONCLUSIONS: This study shows that development of nodular serrated adenomas may depend on the mutation of the K-ras codon 12 gene, whereas development of flat serrated adenomas may not. Additionally, serrated adenomas that occur in the rectum are closely related to the mutation of the K-ras codon 12 gene. K-ras mutations in serrated adenomas may be unaffected by the epigenetic silencing of O6-methylguanine-DNA methyltransferase by promoter hypermethylation.     

A case of septic pulmonary embolism accompanied with tricuspid valve endocarditis and pyogenic spondylitis]

A 54-year-old man was admitted with complaints of high fever and lumbago. A chest radiograph on admission showed bilateral multiple patchy infiltrations. Chest CT showed multiple nodules of various sizes, some with necrotic centers and feeding vessels in the peripheral areas. Some nodules had wedge-shaped consolidations aboutting the pleura. Echocardiography showed vegetation about 12 x 7 mm in size attached to the tricuspid valve. MR imaging of the lumbar vertebrae showed increased signal intensity in the vertebral bodies in L1-4 in T2-weighted images and a further increase of signal intensity by gadolinium enhancement in T1-weighted images. These findings led to a diagnosis of septic pulmonary embolism accompanied with tricuspid valve endocarditis and pyogenic spondylitis irrespective of a negative blood culture. The fever was reduced and the inflammatory findings and chest radiographs were improved by antibiotic therapy, and then tricuspid valvuloplasty was performed. The characteristic CT features of septic pulmonary embolism, mentioned above, can contribute to an accurate and early diagnosis and proper treatment.     

Diffuse alveolar damage after inhalation of zinc oxide fumes]

A 57-year-old man with a 37-year occupational history of welding was admitted for high fever and dyspnea after inhalation of zinc oxide fumes during a period of welding without a protective mask. Chest radiography and CT showed bilateral diffuse ground-glass opacities, and blood gas analysis revealed that PaO2 was 48.1 torr in room air. A transbronchial lung biopsy was done, and revealed diffuse alveolar damage. We diagnosed the case as chemical pneumonia due to the inhalation of zinc oxide, and prescribed prednisolone 40 mg per day. As a result, his symptoms improved within several days. The inhalation of zinc oxide fume usually causes metal fume fever, but chemical pneumonia is also reported on rare occasions. As far as our examination of the literature has disclosed, this is the first report of diffuse alveolar damage after inhalation of zinc oxide fume.