Koujiro Takase

Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase

Phosphorylation of CPI‐17 by Rho‐associated kinase (Rho‐kinase) and its effect on myosin phosphatase (MP) activity were investigated. CPI‐17 was phosphorylated by Rho‐kinase to 0.92 mol of P/mol of CPI‐17 in vitro. The inhibitory phosphorylation site was Thr38 (as reported previously) and was identified using a point mutant of CPI‐17 and a phosphorylation state‐specific antibody. Phosphorylation by Rho‐kinase dramatically increased the inhibitory effect of CPI‐17 on MP activity. Thus, CPI‐17 as a substrate of Rho‐kinase could be involved in the Ca2+ sensitization of smooth muscle contraction as a downstream effector of Rho‐kinase.

Complications of Partial Splenic Embolization in Cirrhotic Patients

In recent years, partial splenic embolization (PSE) has been widely used in patients with cirrhosis and hypersplenism caused by portal hypertension. We investigated the complications associated with PSE cases seen in our hospital. Seventeen cases of liver cirrhosis that had undergone PSE were examined to investigate the complications associated with it. Mean infarcted area of the spleen was 66.2%. Leukocyte and platelet counts in 16 of 17 patients were seen to improve after PSE and persisted for at least one year. The most frequent side effects were abdominal pain (82.4%) and fever (94.1%). Severe side effects were seen in two of those 17 patients. One patient died from acute on chronic liver failure. The other patients contracted bacterial peritonitis and splenic abscess and needed drainage of splenic abscess before recovery. These two cases were in Child-Pugh class B. In conclusions, PSE is a useful treatment for patients with cirrhosis and hypersplenism caused by portal hypertension. However, the possibility of severe complications, especially in patients with noncompensated cirrhosis, should be kept in mind.

Septic endophthalmitis and meningitis associated with Klebsiella pneumoniae liver abscess

We report a female case of septic endophthalmitis and meningitis associated with Klebsiella pneumoniae liver abscess which was thought to be caused by duodeno-biliary reflux related to choledochoduodenostomy. We treated this patient by ultrasonography-guided percutaneous abscess drainage and intravenous administration of third generation antibiotics. However, the visual function of her left eye was eventually lost. Reports of liver abscess with metastatic lesions are rare, and our experience suggests that more physicians should be alert to septic metastatic lesions such as K. pneumoniae liver abscess or bacteremia with complaints of ocular or central nervous system symptoms.

p21WAF1/CTP1 expression and hepatitis virus type.

Since p21WAF1/CIP1 (p21) is a universal inhibitor of cyclin-dependent kinases and is regulated transcriptionally by p53, which is activated by DNA stress, its expression reflects DNA stress in chronic hepatitis. Recently an association with both hepatitis B and C virus and the expression of p53 or p21 was reported. We analyzed p21 expression in 18 cases of HBV-associated chronic liver diseases and 32 cases of HCV-associated chronic liver diseases by immunohistochemical analysis, and investigated the possible association between hepatocyte p21 expression and hepatic inflammation, fibrosis, and especially hepatitis virus type. The p21-positive hepatocytes were more numerous in areas of intense inflammation and spotty necrosis and areas close to fibrosis, and they increased according to the degrees of grading and staging. The p21 labeling index (LI) in patients with liver cirrhosis was significantly higher than that in patients with chronic hepatitis of both hepatitis viral types (5.84 ± 0.61 vs 12.0 ± 0.83, P < 0.0001 in hepatitis B, 10.28 ± 0.80 vs 15.6 ± 1.09, P = 0.0004 in hepatitis C), Furthermore, the p21 LI was significantly higher in HCV-associated liver disease than in HBV-associated liver disease in every group (4.02 ± 0.48 vs 7.74 ± 0.96, P = 0.021 in low grade group, 7.35 ± 0.46 vs 12.8 ± 0.57, P < 0.0001 in high grade, 12.0 ± 0.83 vs 15.6 ± 1.09, P = 0.034 in liver cirrhosis). In, conclusion, p21 expression was up-regulated by the stress of inflammation and fibrosis and might be influenced by viral proteins in human chronic liver disease.

Asymptomatic primary pulmonary hypertension associated with liver cirrhosis

We report a case of asymptomatic primary pulmonary hypertension associated with liver cirrhosis (type B) and portal hypertension found by chance during a preoperative Swan-Gantz catheterization study. Our experience suggests that the actual prevalence of primary pulmonary hypertension associated with liver cirrhosis may be greater than that previously reported. During the follow-up of liver cirrhosis with portal hypertension, we should consider primary pulmonary hypertension, even if the patient is free of symptoms, and a chest X-ray check may be necessary.

The expression and function of Toll-like receptors 3 and 9 in human colon carcinoma

Toll-like receptors (TLRs) are pattern-recognition receptors that are important in immune signaling. TLR recognition of various viral components including double-stranded RNA (TLR3) and unmethylated CpG-DNA (TLR9) plays a crucial role in cell survival. However, TLR expression and function in colon carcinoma cells are not well clarified. We investigated the expression of TLR3 and TLR9 in colon carcinoma cells using immunohistochemical methods. The function of TLR3 and TLR9 signaling in carcinoma cell lines was studied by direct cell stimulation with, or by cell transfection of, polyinosinic-polycytidylic acid (Poly I:C), a synthetic form of dsRNA, and by cell stimulation with CpG-oligodeoxynucleotides (ODNs), respectively. Positive TLR3 and TLR9 immunohistochemical staining was observed in 91 and 86% of human hepatocellular carcinoma (HCC) tissues, respectively. Cell surface stimulation of TLR3 with Poly I:C did not affect cell viability but it did activate NF-κB activity. By contrast, stimulation of intracellular TLRs with transfected Poly I:C significantly induced apoptosis. Cell surface stimulation of TLR9 with CpG-ODNs promoted cell proliferation, and, furthermore, these CpG-ODN TLR9 agonists reduced the cytotoxicity of the anticancer drug adriamycin. Cell surface expression of TLR3 and TLR9 in colon carcinoma cells plays an important role in cell survival. In addition, the proapoptotic activity of intracellularly expressed TLR3 may provide the possibility of using TLR3 agonists as novel clinical cytotoxic agents against colon carcinoma cells.

Primary Localized Amyloidosis of the Small Intestine Presenting as an Intestinal Pseudo-obstruction: Report of a Case

Abstract A 47-year-old man with primary amyloidosis confined to the small intestine is reported. Thickening of the folds and multiple polypoid protrusions were found in the duodenum by upper gastrointestinal endoscopy. Because the patient presented with a persistent intestinal pseudo-obstruction, partial jejunectomy was performed. Histological examination of the resected tissue revealed massive deposits of amyloid throughout the jejunal wall. Neither a predisposing condition nor any other sites of deposition were found, and primary amyloidosis of the small intestine was diagnosed. This rare form of amyloid deposition should be recognized so that an early diagnosis can be made.

The emerging role of caspase inhibitors in gastrointestinal cancers.

Apoptosis is an important process in a wide variety of biological systems, and dysregulation of apoptosis is implicated in many human diseases, including malignancy. In fact, cancer cells demonstrate resistance to a variety of apoptotic stimuli, so that an understanding of the inhibitory mechanisms of apoptosis is particularly important. Recently, researchers have focused on endogenous cellular inhibitors of caspases and found that caspases can be controlled by a variety of inhibitors, such as the inhibitor of apoptosis (IAP) family, and FLICE/caspase 8-inhibitory protein (FLIP), which directly interact with caspases. The IAP family is a widely expressed group of inhibitors, from both physiologic and phylogenic perspectives. The strongest evidence for IAP involvement in cancer is seen with survivin and X-chromosome-linked IAP (XIAP), and the caspase inhibitory effect of XIAP is stronger than that of survivin. Survivin promotes cell proliferation. Inhibition of caspase 8 by FLIP or the phosphatidylinositol 3-kinase/AKT pathway is also an important mechanism for the inhibition of apoptosis. This review summarizes the current and rapidly expanding knowledge concerning the biological functions of caspase inhibitors and the mechanisms for counteracting apoptosis, especially in malignant gastrointestinal cells.

CASE REPORT: Hepatocellular Carcinoma Associated with Adult-Type Citrullinemia

Hypercitrullinemia is a rare hereditary metabolic disorder caused by the deficiency in the activity of argininosuccinate synthetase. McMurrey et al first reported this disease in infants (1) and Saheki et al classified three types on the basis of qualitative and quantitative analysis of argininosuccinate synthetase (2). The classic neonatal and infantile forms were assigned to type I (abnormal kinetics of the enzyme) and III (undetectable or extremely low levels of the enzyme). Biochemically, the defect of the enzyme in the classical types is found in all tissues and/or cells where argininosuccinate synthetase is expressed (3). Analysis of the amplified cDNA from 14 neonatal/infantile type III citrullinemia patients identified mutations in the mRNA that are heterogeneous (4). Type II citrullinemia is an adult-onset type and is clinically characterized by a sudden onset of consciousness disturbance, a high serum citrulline concentration, and hyperammonemia. Most of this type of citrullinemia occurs in Japan unlike in the United States and Europe. Type II citrullinemia is characterized by a quantitative decrease of argininosuccinate synthetase only in the liver, while argininosuccinate synthetase levels in other tissues, such as kidney, brain, and fibroblasts, are normal. The hepatic content of the enzyme is about 10% of control value, but the translatable mRNA level for the enzyme is similar to the control value and there is no mutation in the argininosuccinate synthetase mRNA. Thus, it is confirmed that the liver contained the normal amount of mRNA coding for argininosuccinate synthetase, but there was increased degradation of the enzyme or inhibited translation (5–8). Although there are reports of the patients of type II citrullinemia complicated by hepatocellular carcinoma, the details were not well elucidated (7, 9). Here, we report on a patient with adult type citrullinemia who developed hepatocellular carcinoma after 29 years of follow-up, and we analyzed argininosuccinate synthetase in hepatocellular carcinoma tissues.

A case of acute intermittent porphyria with acute pancreatitis

SummaryA case of acute pancreatitis in a 29-year-old female associated with an attack of acute intermittent porphyria (AIP) is reported. Following the attack of AIP, serum pancreatic amylase originating from the pancreas increased transiently, and mild swelling of the pancreas was detected by ultrasonography. On this basis acute pancreatitis was diagnosed. Additionally, this patient had mild hepatic dysfunction. Laparoscopy disclosed diffuse slightly dark bluish pigmentation on the irregular surface of the liver. Mild fibrous dilatation of the portal area with lymphocytic infiltration was seen histologically. Acute pancreatitis and hepatic damage with AIP is extremely rare, however it is possible that these findings are etiologically connected in this patient.