Jun activation domain binding protein 1 is overexpressed from the very early stages of hepatocarcinogenesis.

BACKGROUND: As is known for many types of human cancers, the hepatocellular carcinoma (HCC) associated with chronic liver disease shows an obvious multistage process of tumor progression. Despite the demonstrated importance of cell-cycle regulators in tumor biology, there have only been a few studies of their role in multistep hepatocarcinogenesis. Recently, we reported that a high level of p27(Kip1) expression is evident from the very early stages of hepatocarcinogenesis. METHODS: In the present study, expression of p27(Kip1) and Jun activation domain binding protein-1 (Jab1), which is a key molecule involved in posttranslational regulation of p27(Kip1), was evaluated in surgically resected specimens of 8 dysplastic nodules (DNs), 16 early HCCs, and 126 classical HCCs. RESULTS: Immunohistochemistry revealed no Jab1 expression in the majority of hepatocytes in noncancerous normal liver tissue and cases of chronic hepatitis or cirrhosis. In contrast, Jab1 was overexpressed in 50% (4/8) and 50% (8/16) of DNs and early HCCs, respectively, and the labeling index was increased in line with the degree of loss of differentiation in classical HCCs. Real-time quantitative reverse transcription polymerase chain reactions revealed the Jab1 mRNA levels in all tested early and well-differentiated HCCs to be increased compared with matched nontumorous liver specimens. The Spearman coefficient pointed to a high correlation between p27(Kip1) and Jab1 mRNA expression levels (P = 0.0014). CONCLUSIONS: Jab1 expression, as well as p27(Kip1) upregulation, is evident from the very early stages of hepatocarcinogenesis, suggesting that Jab1 could be a diagnostic marker and a treatment target for precancerous lesions and early HCCs.

Analysis of Bordetella pertussis agglutinin titers during an outbreak of pertussis at a university in Japan.

In 2007, a large outbreak of pertussis occurred at a university in Japan. Initially, a student, suffering from nocturnal cough and post-tussive vomiting for 3 weeks was diagnosed with pertussis. During the subsequent outbreak, 361 university students and staff members presented with a primary complaint of a cough. In the present study, we analyzed bacterial agglutinin titers against two Bordetella pertussis strains, Yamaguchi (epidemic strain) and Tohama (vaccine strain), in 310 patients with a cough and evaluated its diagnostic accuracy for adolescent and adult pertussis. These serological analyses showed a significant difference (P<0.001) in the levels of Yamaguchi agglutinin titer, but not in those of Tohama agglutinin titer, between patient and healthy adult groups. Therefore, the bacterial agglutination assay against strain Yamaguchi may be a useful tool for diagnosis of adolescent and adult pertussis, especially in young adults, when an agglutinin titer cutoff value of >or=160x is used in combination with clinical symptoms and other clinical laboratory tests.

p27(Kip1)is overexpressed in very early stages of hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) associated with chronic liver disease evolves from precancerous lesions and early HCC to more malignant forms. Despite the demonstrated importance of cell-cycle regulators in tumor biology, there have been few studies of their role in multistep hepatocarcinogenesis. Expression of p27(Kip1) and a degradation pathway associated protein, S-phase kinase-interacting protein 2 (Skp2), was therefore evaluated in surgically resected specimens of eight adenomatous hyperplasias, 16 early HCC and 126 classical HCC. Immunohistochemistry revealed no p27(Kip1) expression in the majority of hepatocytes from normal and cirrhotic liver, whereas positive staining for p27(Kip1) protein was found in 75.0% and 93.8% of adenomatous hyperplasias and early HCC, respectively. The average p27(Kip1) labeling indices (LI) for adenomatous hyperplasias, early HCC, well differentiated HCC, moderately differentiated HCC and poorly differentiated HCC were 36.99, 43.59, 47.73, 49.24, and 30.21, respectively. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses confirmed the increases. Skp2 LI were also significantly elevated in accordance with stepwise progression of hepatocarcinogenesis. Increased expression of Skp2 mRNA was observed most frequently in less differentiated tumors and Kaplan-Meier survival analysis showed a significantly association with a poor prognosis (P = 0.0496). In conclusion, a high level of p27(Kip1) expression is evident from early stages of hepatocarcinogenesis, indicating that this parameter could be a useful diagnostic marker for precancerous lesions and early HCC. In addition, Skp2 expression correlates with tumor dedifferentiation and may contribute to biological aggression in HCC.

Analysis of heart rate variability as an index of noncardiac surgical stress.

Measurement of heart rate variability (HRV) is useful in assessing the function of the autonomic nervous system and in staging of clinical diseases. The purpose of this study is to assess a feasibility of HRV for evaluating surgical stress during the noncardiac perioperative period. Standard deviation of normal-to-normal RR intervals (SDNN) and HRV triangular index derived from 24-h Holter ECC were measured in 24 patients undergoing digestive surgery. Holter ECG was performed at 1 day before operation, the first day (postoperative day 1: POD1), and the 7th day (POD7) after operation. Indices of HRV were compared with factors influencing surgical stress, such as duration of the operation and amount of blood loss during the operation, and postoperative complications. The SDNN and HRV triangular index decreased significantly on POD1 and recovered on POD7 (P < 0.05). Heart rate variability indices correlated significantly to duration and blood loss of operation (both P < 0.05). In 7 patients with postoperative complications, HRV indices were statistically lower than those in patients without complications on POD1 (P < 0.05). Our results indicate that HRV may provide useful information with respect to surgical stress.

Heart rate variability for evaluating surgical stress and development of postoperative complications.

Heart rate variability (HRV) has recently been used to detect autonomic nerve tone, which is affected by various stresses. To test out hypothesis that HRV can determine surgical stress, we examined perioperative HRV in 30 patients with surgical treatment. Relations between HRV and factors of surgical stresses, such as duration of the operation, amount of blood loss at the operation, and developments of complications, were evaluated. Mean heart rate (HR) increased and other HRV indices decreased postoperatively. Most indices correlated significantly to the duration of the operation and amount of blood loss at the operation on postoperative day 1. Only the standard deviation of normal to normal RR intervals (SDNN) and HRV triangular index showed significantly low values in complicated patients. HRV measurement in the perioperative period showed a significant relation to surgical stress. The present results indicated that HRV may provide useful information with respect to surgical stress.

Colo-colic intussusception associated with Henoch-Schönlein purpura in adults.

Henoch-Schönlein purpura (HSP) is often seen in childhood and is a self-limiting illness, and complication with intussusception is rare in adults. The case is reported of a 74-year-old man who was diagnosed with intussusception with HSP by ultrasonography on day of admission. Conservative therapy was started. However, his abdominal symptoms worsened, so he underwent laparotomy 3 days after admission. Histological study of the resected specimens demonstrated necrosis in the intussuscepted colon induced by HSP vasculitis. Bowel necrosis with intussusception in adult HSP is rare and might easily be overlooked. Thus special attention should be paid to gastrointestinal manifestations and, in an abdominal emergency, timely surgical intervention is life-saving.

Ischemic preconditioning of the murine liver protects through the Akt kinase pathway.

Hepatic ischemia-reperfusion (I/R) injury occurs in the settings of transplantation, trauma, and elective liver resection. Ischemic preconditioning has been used as a strategy to reduce inflammation and organ damage from I/R of the liver. However, the mechanisms involved in this process are poorly understood. We examined the role of the phosphatidylinositol 3 (PI3) kinase/Akt-signaling pathway during hepatic ischemic preconditioning (IPC). Prior to a prolonged warm ischemic insult, BALB/c mice were subjected to a 20-minute IPC period consisting of 10 minutes of ischemia and 10 minutes of reperfusion. Mice undergoing IPC demonstrated a significantly greater level and earlier activation of Akt in the liver compared with control animals. IPC also resulted in markedly less hepatocellular injury and improved survival compared with control animals. Akt activation associated with hepatic IPC suppressed the activity of several modulators of apoptosis, including Bad, glycogen synthase kinase beta, and caspase-3. In addition, IPC also inhibited the activities of c-Jun N-terminal kinase and nuclear factor kappaB after I/R. Pretreatment of mice with PI3 kinase inhibitors completely abolished Akt phosphorylation and the protective effects seen with IPC. In conclusion, these results indicate that the PI3 kinase/Akt pathway plays an essential role in the protective effects of IPC in hepatic I/R injury. Modulation of this pathway may be a potential strategy in clinical settings of ischemic liver injury to decrease organ damage.

Improved microcirculatory effect of D-allose on hepatic ischemia reperfusion following partial hepatectomy in cirrhotic rat liver.

D-allose, one of the rare sugars produced from D-psicose, has been shown to be effective against reperfusion injury after ischemia and partial hepatectomy in cirrhotic rat liver by improving remnant liver blood flow and survival rates, and decreasing liver enzyme levels and liver tissue injury levels. These findings demand further study of the clinical implications of this sugar in view to the advancing fields of liver surgery and transplantation.

Compression of the common hepatic duct by the right hepatic artery.

Magnetic resonance (MR) cholangiography has been used wildly as preoperative examination before laparoscopic cholecystectomy (LSC). However, cases that suggested the stenotic lesion of extrahepatic bile duct are not so rare in MR cholangiography. When stenosis is found, further examination is needed to avoid the possibility of bile duct cancer. We reported a case in which the stenotic lesion was diagnosed compression of the common hepatic duct by the right hepatic artery by multislice CT (MCT) cholangiography.

[TS-1 therapy via intestinal catheter used for tube feeding in a patient with gastric cancer after total gastrectomy].

The patient was a 76-year-old man having gastric cancer with peritoneal dissemination. He underwent total gastrectomy for resection of the primary tumor and improvement of the oral intake. He developed ileus and peritonitis after the surgery, which necessitated two additional operations. An intestinal stoma was thus therefore created using a catheter for tube feeding, and tube feeding was initiated after the surgery. Nutrients, as well as TS-1 (taken out of the capsule; 80 mg/day) were administered via the catheter for tube feeding. This therapy was followed by a reduction in tumor marker levels and improvement of the patient's performance status (PS), after which the patient could be discharged. He stayed at home for about 8 months, with a much-improved quality of life during this period. We concluded that the TS-1 therapy via the catheter used for alimentation was effective for the treatment of cancer in this patient. We report our experience with this case, in which tube feeding became necessary after total gastrectomy, but administration of TS-1 via the same catheter used for alimentation improved the patient's PS and made it possible for him to receive chemotherapy at home.

Role of NAD(P)H oxidase- and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II.

Reactive oxygen species (ROS) participate in cardioprotection of ischemic reperfusion (I/R) injury via preconditioning mechanisms. Mitochondrial ROS have been shown to play a key role in this process. Angiotensin II (Ang II) exhibits pharmacological preconditioning; however, the involvement of NAD(P)H oxidase, known as an ROS-generating enzyme responsive to Ang II stimuli, in the preconditioning process remains unclear. We compared the effects of 5-hydroxydecanoate (5-HD; an inhibitor of mitochondrial ATP-sensitive potassium channels), apocynin (an NAD(P)H oxidase inhibitor), and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol; a membrane permeable radical scavenger) on pharmacological preconditioning by Ang II in rat cardiac I/R injury in vivo. Treatment with a pressor dose of Ang II before a 30-minute coronary occlusion reduced infarct size as determined 24 hours after reperfusion. The protective effects of Ang II were eliminated by pretreatment with 5-HD or apocynin, similar to tempol. Both 5-HD and apocynin suppressed the enhanced cardiac lipid peroxidation and activation of the apoptosis signal-regulating kinase/p38, c-Jun NH2-terminal kinase (JNK) pathways, but not the Raf/MEK/extracellular signal-regulated kinase pathway, elicited by acutely administered Ang II. Apocynin but not 5-HD suppressed Ang II-induced augmentations of the NAD(P)H oxidase complex formation (p47phox, p22phox, and Rac-1) and its activity in the heart. Finally, 5-HD suppressed superoxide production by isolated cardiac mitochondria without any effect on their respiration. These results suggest that the preconditioning effects of Ang II for cardiac I/R injury may be mediated by cardiac mitochondria-derived ROS enhanced through NAD(P)H oxidase via JNK and p38 mitogen-activated protein kinase activation.

Preoperative assessment of the aberrant bile duct using multislice computed tomography cholangiography.

BACKGROUND: This study aimed to determine the frequency of anatomic variations of bile ducts (aberrant bile ducts) using multislice helical computed tomography (MCT) cholangiography. METHODS: MCT scanning was performed after slow infusion of 100 mL meglumine iotroxate. Overlapping axial images, taken at 0.5-mm intervals, were reconstructed to create a multiplanar reconstruction with volume rendering. We analyzed anatomical variations of the biliary tree by MCT cholangiography. RESULTS: In a total of 113 patients, MCT cholangiography provided clear images of aberrant bile ducts in 18 patients. Major type (draining a particular segment of the liver) was found in 9 cases (8%) and minor type (draining a particular subsegment of the liver) in 9 cases (8%). CONCLUSIONS: Preoperative MCT cholangiography provides important information about the precise biliary anatomy and can reveal unexpected aberrant bile ducts prior to biliary surgery, especially laparoscopic cholecystectomy.

[A case of multiple pulmonary metastases from rectal cancer effectively treated by TS-1 and low-dose CDDP therapy].

We report a patient with multiple pulmonary metastases from rectal cancer effectively treated with TS-1 and low-dose CDDP combination chemotherapy. The patient was a 61-year-old man with rectal cancer and multiple pulmonary metastases. He had undergone abdominoperineal excision of the rectum at another hospital before this hospitalization. After the operation, we treated the patient by the combination chemotherapy of TS-1 and low-dose CDDP during his hospital stay and in the outpatient clinic after hospital discharge. After the chemotherapy was started, tumor markers decreased, and finally were in the normal range. The pulmonary metastatic lesions were remarkably reduced on CT, and the effect of this therapy was PR. No severe side effect was observed throughout the treatment. This combination chemotherapy is considered to be an effective therapy for colorectal cancer with good QOL.

D-Allose has a strong suppressive effect against ischemia/reperfusion injury: a comparative study with allopurinol and superoxide dismutase.

BACKGROUND/PURPOSE: D-Allose, a rare sugar, is one of the potent inhibitors of ischemia/reperfusion injury of the rat liver. To investigate the potency of this powerful agent we examined its effect against ischemia/reperfusion injury and compared it to that of allopurinol and superoxide dismutase. METHODS: Male Lewis rats were given water ad libitum preoperatively for 12 h and anesthetized by isoflurane inhalation anesthesia. Drugs were administered through a polyethylene catheter inserted into the portal vein for 2 h (D-allose), 10 min (allopurinol), or 5 min (superoxide dismutase) before ischemia, and the livers were then subjected to 70% ischemia, induced by crossclamping the vessels to the lateral and median lobes of the liver for 90 min. Rats were divided into four groups: group 1, pretreated with vehicle (normal saline); group 2, treated with D-allose; group 3, treated with allopurinol; and group 4, treated with superoxide dismutase. The effects of the drugs were evaluated by liver hemodynamics, neutrophil count, myeloperoxidase, liver enzymes, and histological studies. RESULTS: D-Allose improved liver hemodynamics (P < 0.001) and postischemic animal survival (P < 0.05) significantly compared with the control group and nonsignificantly compared with the allopurinol and superoxide dismutase groups. Myeloperoxidase activity in the postischemic liver tissue was decreased significantly (P < 0.05) by D-allose compared with all other treatment and control groups. Neutrophil count was also significantly (P < 0.05) decreased in the D-allose group compared with than that in the control group, as well as the superoxide dismutase group. Only D-allose produced a statistically significant decrease in the level of liver enzymes, compared with levels in the control group. CONCLUSIONS: The moderately protective effect of D-allose, which caused no clinical side effects, is encouraging. D-Allose had the best protective effect against neutrophil-related postischemic injury of the liver tissue, followed by allopurinol and superoxide dismutase. However, a more extensive study is needed to ensure the effects as well as the mechanisms of the effect of this rare sugar.

Evaluation of liver function for hepatic resection for hepatocellular carcinoma in the liver with damaged parenchyma.

BACKGROUND: Liver functional parameters, including the Child-Pugh score and indocyanine green clearance (ICG), and volumetric parameters influencing postoperative liver function were evaluated with the aim of obtaining standardardized criteria for selecting patients for, and deciding the extent of, hepatectomy for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The study population consisted of 120 patients with HCC undergoing hepatic resection excluding those with more than 3000 ml of intraoperative bleeding. Patients were classified as grades A, B, or C on the basis of, respectively, a Child-Pugh score of 5 or 6, 7-9, or >or=10 and were assigned to group D (postoperative liver dysfunction) or group N (no complication). Postoperative complications included massive ascites, pleural effusion, or hyperbilirubinemia. For each grade, the standardized estimated liver remnant ratio (STELR) was determined as the ratio of the liver remnant volume (estimated by computerized tomography) to the standardized total liver volume (STLV), estimated from the body surface area using the equation: liver volume [cm(3)] = 706 x body surface area [m(2)] + 2.4. The ICG retention rate at 15 min after injection (ICGR15) was then plotted against the STELR for each grade and a demarcation line separating patients in groups N and D was determined statistically by discriminant analysis. RESULTS: For grade A patients, the equation of the demarcation line was ICGR15 = 27.5 x STELR + 1.9 (Wilks' Lambda: 0.667, P < 0.001), indicating that, for safe hepatic resection in patients with an ICGR15 of 10%, the STELR should be greater than 0.29. In contrast, for grade B patients, the equation was ICGR15 = 72 x STELR - 22.1 (0.589, P < 0.001), indicating that, in patients with a 10% ICGR15, the STELR should be greater than 0.44, a larger value than in grade A patients. The number of grade C patients was too small for analysis. CONCLUSIONS: By combining the Child-Pugh score, ICG clearance, and liver volumetric parameters, criteria for the selection of patients for hepatic resection for HCC were established.

Protective effects of D-allose against ischemia reperfusion injury of the rat liver.

BACKGROUND/PURPOSE: D-allose, a rare sugar, has been reported to inhibit segmented neutrophil production without causing any significant detrimental clinical effects. Our previous study demonstrated the immunosuppressive effect of D-allose in a rat model of liver transplantation. Neutrophils are closely involved in the process of hepatic ischemia/reperfusion (I/R) injury. One possible mechanism is the adherence of neutrophils to the hepatic sinusoidal endothelium following microcirculatory failure. METHODS: The present study investigated the effects of D-allose on the involvement of neutrophils, with particular emphasis to the microcirculation in a model of hepatic I/R. Ischemia was induced by occluding the hepatoduodenal ligament for 90 min. D-allose was infused 2 h before ischemia. Normal saline was infused in the control group. Liver tissue blood flow (LTBF) and portal venous flow (PVF) were measured before and after ischemia. Myeloperoxidase (MPO) and ATP were measured at, before inducing ischemia, at the end of ischemia, and at the end of 2-h reperfusion. Liver enzyme analysis and histology were done at the end of reperfusion. Post-reperfusion animal survival was followed for 15 days. RESULTS: D-allose significantly improved the liver hemodynamics and post-reperfusion animal survival, with a significant decrease in liver tissue MPO, liver enzymes, and the number of neutrophils. ATP level was improved significantly in the D-allose group. Histology revealed significant sinusoidal congestion and tissue necrosis after 2-h reperfusion in the control group. CONCLUSIONS: D-allose exerted its protective effects against liver damage incurred when the liver was injured by warm ischemia and reperfusion mainly by the suppression of activated neutrophils.

Pretreatment with 8-methoxypsoralen, a potent human CYP2A6 inhibitor, strongly inhibits lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in female A/J mice.

Human CYP2A6 has been recognized as being involved in the mutagenic activation of promutagens such as the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Methoxsalen (8-methoxypsoralen) was reported to inhibit CYP2A6. In the present study, the inhibitory effects of methoxsalen on NNK-induced lung tumorigenesis in female A/J mice were examined. Female A/J mice were treated with methoxsalen at doses of 50 or 12.5 mg/kg body weight, given by stomach tube, daily for 3 days. One h after the final treatment, NNK was injected i.p. at a dose of 2 mg/mouse. The experiments were terminated 16 weeks after the first methoxsalen treatment, and lung adenomas were analyzed. Pretreatment of methoxsalen significantly reduced tumor incidence from 93.8% to 16.7% (50 mg/kg) and 20.0% (12.5 mg/kg), and tumor multiplicity from 5.97 to 0.23 (50 mg/kg) and 0.25 (12.5 mg/kg) tumors/mouse. These results clearly demonstrated that methoxsalen, a potent human CYP2A6 inhibitor, is a strong chemopreventive agent against NNK-induction of lung tumorigenesis.