[MRI-CT fusion image navigation during surgery for inverted papilloma].

We report two cases of intraoperative computer-aided surgery using magnetic resonance imaging (MRI)/computed tomography (CT) fusion imaging for inverted papilloma (IP). Case 1: IP had spread to the frontal recess/sinus so we chose a combined endoscopic sinus surgery (ESS) and external approach. Case 2: For a maxillary sinus tumor, we combined ESS and the adjuvant external (Caldwell-Luc) procedure. This is helpful to surgeons when, shifting fusion imaging when opening the frontal sinus bone to obtain CT data, and shifting to MRI to detect the tumor pedicle, then approaching the bone defect using MRI-CT fusion imaging (50-50%).

Prognostic indicators estimated by (99m)Tc-GSA in acute liver damage.

A prognostic estimation formula of acute liver damage was evaluated by using clinical data and technetium-99m-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin ((99m)Tc-GSA) scintigraphy in order to determine operability for orthotopic liver transplantation (OLT). Forty-six patients hospitalized for acute liver damage were divided into survival (n=35) and non-survival (n=11) groups. Univariate and multivariate analyses were used to identify significant factors that affected prognosis. Logistic regression analysis was performed to predict prognosis with effective factors. Ten independent factors with significant differences were identified and further analyzed for significance by logistic regression analysis. Among the 10 factors, age and LHL15/HH15 were identified as having meaningful differences for predicting convalescence. The following formula was developed: A negative value for R indicates non-survivals, and a positive value indicates survivals. The mortality rate was calculated as=1/(1+e(R)). The sensitivity was 0.909, specificity was 1.000, and accuracy was 0.978. The reliability of this formula was as good as that of another formula presented previously by the Intractable Liver Diseases Study Group of Japan. The use of (99m)Tc-GSA for estimating the prognosis of acute liver damage is useful, especially before the onset of hepatic encephalopathy.

Exophytic pedunculated gastrointestinal stromal tumor with remarkable cystic change.

A 59-year-old man with bloody stools, and previously diagnosed with sigmoid colon carcinoma, visited our hospital. Preoperative abdominal ultrasonography (US) showed another tumor, with an uneven irregular surface, measuring about 9 x 5 cm, below the left hypochondrium. The tumor consisted of several cysts. Abdominal computed tomography (CT) showed a multicystic tumor attached to the stomach, and its septum and marginal region were intensely stained on contrast imaging. On magnetic resonance imaging (MRI), low and markedly high signals were revealed in the tumor on T1-weighted and T2-weighted sequences, respectively. Contrast imaging of the upper digestive tract showed extramural compression of the greater curvature of the antral stomach by the tumor. The tumor was partially imaged by endoscopic ultrasonography (EUS), but continuity to the stomach was not confirmed. On abdominal angiography, the tumor was slightly stained via the gastroepiploic arteries. Surgical treatment was performed to excise both the gastric tumor and the sigmoid colon carcinoma. The gastric tumor was removed with gastric wall tissue where the tumor was attached to a 2-cm pedicle. It was multicystic, contained watery fluid, and had a smooth outer surface. Histologically, the tumor consisted of multiple irregular cysts without epithelial lining, and solid epitheloid cell nests in between. The tumor cells had clear or eosinophilic cytoplasm and round nuclei. No mitotic figures were seen. The tumor cells in the pedicle were connected with the muscularis propriae of the stomach. Immunohistochemistry showed c-kit-positive, CD34-positive smooth muscle actin (SMA)-negative, and S-100-negative staining of tumor cells. The final diagnosis was gastrointestinal stromal tumor (GIST).

Intracystic hemorrhage of a simple liver cyst mimicking a biliary cystadenocarcinoma.

Simple liver cysts are rarely complicated by intracystic hemorrhage. We encountered a case of simple liver cyst that was morphologically similar to biliary cystadenocarcinoma, which was complicated by asymptomatic intracystic hemorrhage and successfully treated by right lobectomy. A large cystic lesion of the liver was detected in a 57-year-old woman during a mass screening health check. Abdominal ultrasonography (US) revealed that the cystic lesion, containing many hyperechoic papillary structures, occupied almost the entire region of the right hepatic lobe. In addition, a round mural nodule, measuring approximately 5 cm in diameter, was detected in the cystic wall. Abdominal computed tomography (CT) revealed that the inner part of the cystic lesion showed homogeneous low density, but CT did not show the round nodule detected by US. On T1-weighted sequence of magnetic resonance imaging (MRI), the lesion showed homogeneous high signals, together with a low-signal tumorous lesion in the cystic wall. T2-weighted sequence of MRI showed unhomogeneous high signals, together with high signals in the tumorous part. These findings did not exclude the possibility of a malignant cystic tumor, such as biliary cystadenocarcinoma. Therefore, right lobectomy was performed. Histological examinations of resected tissue specimens revealed that the lesion was a liver cyst containing a large amount of blood clot, and that the tumorous lesion detected by US and MRI was a large mass of blood clot which was partly liquefied. This case indicates the diagnostic importance of the morphological discordance between CT and US or MRI findings for liver cyst containing a large amount of blood clot.

Differential expression of decay-accelerating factor isoforms in the digestive tract of guinea pig.

Decay-accelerating factor (DAF, CD55), one of the membrane-binding regulators of complement activation, prevents host cells from the autologous complement-mediated attack. However, specific localization of DAF in the different layers of the digestive tract has not been defined. Using a crypt isolation procedure, we separated epithelium from the remnant stromal tissue and assessed the expression of DAF isoforms in the two layers in the guinea pig digestive tract. Both Northern hybridization and immunohistochemistry revealed DAF was preferentially expressed in the small intestinal epithelium compared to the stomach and colon. Reverse-transcriptase PCR demonstrated that the glycosyl-phosphatidylinositol (GPI)-anchored isoforms are predominant over the transmembrane (TM) isoforms in all digestive epithelium. However, there was no difference between GPI-anchored type and TM type in the stromal tissue. In conclusion, DAF was found to be primarily expressed in the small intestinal epithelium with isoforms differing between the epithelium and stromal tissue, suggesting differential roles in the guinea pig digestive tract.

A case of pancreaticoduodenal artery aneurysm causing pancreatic pseudotumour and duodenal obstruction.

This case report describes a ruptured pancreaticoduodenal artery aneurysm (PDAA) causing pancreatic pseudotumour and duodenal obstruction. A 59-year-old man was referred to our hospital with a chief complaint of frequent vomiting without abdominal pain. Because a mass lesion 10 cm in diameter was palpated in the right para-umbilical region and found in the head of the pancreas on computerized tomography (CT) and ultrasonography, malignant tumour of the pancreas or tumour-forming pancreatitis was strongly suspected, and further examination was performed.Magnetic resonance imaging (MRI) results suggested subacute haematoma inside the mass. On angiography, an aneurysm 8 mm in diameter was found in the posterior superior pancreaticoduodenal artery (PSPD). Since an ultrasound-guided percutaneous needle biopsy from the solid part of the mass indicated no malignancy, the lesion was considered an inflammatory pseudotumour in the head of pancreas due to ruptured aneurysm. Bypass surgery was planned, but the tumour shrank significantly with conservative treatment. Obstruction disappeared completely without surgery 4 weeks after the first symptom.

Liver transplantation-associated hypercalcemia followed by acute renal dysfunction.

A 34-year-old woman with liver insufficiency due to glycogen storage disease III underwent a living spousal liver transplantation. Soon after the successful operation, moderate hypercalcemia along with hyperbilirubinemia emerged without clarified reasons. The hypercalcemia persisted for over a month despite calcitonin treatment and the serum calcium level surged to 13.2 mg/dl with albumin correction. Renal dysfunction was indicated by an acute increase in serum creatinine (approximately 0.8 to approximately 2.8 mg/ml), which was assumed to be hypercalcemia-induced and was effectively treated with bisphosphonate, pamidronate (30 mg, i.v.). Recent topics related to transplantation-associated hypercalcemia are discussed.

Taurochenodeoxycholic acid induced biphasic hepatotoxicity in isolated perfused rat liver: roles of Ca2+ and calpain.

BACKGROUND/AIMS: We examined taurochenodeoxycholic acid-induced hepatotoxicity with reference to Ca2+ and calpain involvement, intracellular bile acid content, and zone specificity in isolated perfused rat liver. METHODOLOGY: Taurochenodeoxycholic acid or chenodeoxycholic acid was infused into the portal vein and lactate dehydrogenase release, a marker of hepatocyte injury, in the effluent and bile acid output were measured in the presence and absence of either nickel, a membranous Ca2+ channel blocker, or calpain inhibitor in isolated perfused rat liver. RESULTS: Taurochenodeoxycholic acid induced a significant and transient increase (first peak; 4 min) and subsequent time- and dose-dependent elevation in lactate dehydrogenase release which was proportional to accumulated bile acids in the liver. Although the first peak was significantly suppressed by pretreatment with nickel, the subsequent release was not reduced. Lactate dehydrogenase release at 15, 20, and 25 min was significantly suppressed by the calpain inhibitor. Numbers of damaged hepatocytes stained with trypan blue were significantly increased in the periportal region (zone 1) compared with the pericentral region (zone 3) and these cells were consistently stained with anti-calpain antibody. CONCLUSIONS: Taurochenodeoxycholic acid causes both transient damage and subsequent increasing hepatotoxicity which are respectively dependent on Ca2+ influx via membranous Ca2+ channels and calpain, with the periportal region being more susceptible.

Clinical factors related to long-term administration of sorafenib in patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib has been approved in the indication of unresectable hepatocellular carcinoma, but there are many cases in which administration of the drug is discontinued due to severe side effects. In this study, we compared the characteristics of patients who continued and discontinued sorafenib. METHODS: Ninety-six patients (75 men and 21 women) were initiated on sorafenib from July 2009 through September 2011. The patient characteristics of interest included gender, age, etiology, Child-Pugh classification, treatment history and frequency, and levels of α-fetoprotein, des- gamma-carboxy prothrombin, aspartate amino acid transferase, and alanine aminotransferase. Duration of administration of sorafenib and reasons for its discontinuation were compared. RESULTS: Median overall survival was 11.8 months. Discontinuation of sorafenib within 90 days was identified as an independent prognostic factor for overall survival on multivariate analysis (P < 0.0001). Transarterial chemoembolization performed six times or more (P = 0.013) was also identified as an independent factor contributing to discontinuation of sorafenib within 90 days in multivariate analysis. Patients who received sorafenib for ≥90 days had significantly longer overall survival than those who discontinued it (P < 0.0001). CONCLUSION: Prolonged treatment with sorafenib is an important factor in achieving extended overall survival. We recommend starting sorafenib before latent liver damage has occurred as a result of too many transarterial chemoembolization procedures.

Molecular epidemiology and genetic history of European-type genotype 3 hepatitis E virus indigenized in the central region of Japan.

In Mie prefecture in Japan, 12 cases of sporadic hepatitis E occurred from 2004 to 2011. Mie prefecture is located in the central region of Japan, far from the most prevalent regions of hepatitis E virus (HEV) infection in Japan, the north and northeastern part. These 12 cases did not have any common risk factors of HEV infection. We analyzed the molecular epidemiology of the cases in Mie prefecture. We obtained the nucleotide sequences of the HEV strains and analyzed them with the sequences of other HEV strains by phylogenetic and coalescent analyses. Japan-indigenous genotype 3 HEV strains were divided into two major subtypes, namely, 3a and 3b; one minor subtype, 3e; and a few other unassigned lineages. The Japan-indigenous subtype 3e strains were closely related to European subtype 3e HEV strains and were comparatively rare in Japan; however, eight strains of the 12 cases we examined belonged to subtype 3e, indicating a close phylogenetic relationship, despite the lack of common risk factors. Coalescent analyses indicated that the Mie 3e strains seemed to have intruded into Mie prefecture about 10 years ago. Sporadic acute hepatitis E cases caused by the 3e strains occurred consistently from 2004 to 2011 in Mie prefecture. This is the first report of unexpected persistent occurrence of hepatitis by the European-type genotype 3 HEV, subtype 3e, in a country outside of Europe. Phylogenetic and coalescent analyses traced the history of the indigenization of the Mie 3e strains from Europe. Because hepatitis E cases caused by 3e strains are relatively rare in Japan, molecular evolutionary analyses of HEV infection in Mie prefecture is important for preventing a future hepatitis endemic or epidemic by 3e strains in Japan.

Bcl11b heterozygosity leads to age-related hearing loss and degeneration of outer hair cells of the mouse cochlea.

BCL11B/CTIP2 zinc-finger transcription factor is expressed in various types of cells in many different tissues. This study showed that BCL11B is expressed in the nucleus of the outer hair cells of the mouse cochlea, degeneration of which is known to cause deafness and presbycusis or age-related hearing loss (AHL). We tested whether or not Bcl11b heterozygosity would affect AHL in mice. Analysis of auditory brainstem responses revealed AHL in Bcl11b (+/-) heterozygous, but not wild-type, mice, which was evident as early as 3 months after birth. Histological abnormalities were observed in the outer hair cells of the Bcl11b (+/-) mice at 6 months of age with hearing loss. These results suggest that the AHL observed in Bcl11b (+/-) mice is the result of impairment of the outer hair cells and that BCL11B activity is required for the maintenance of outer hair cells and normal hearing.

Fine mapping of Ahl3 affecting both age-related and noise-induced hearing loss.

A region in the vicinity of D17Mit119 on mouse chromosome 17 harbors a susceptibility gene, designated as Ahl3, to age-related hearing loss (AHL). We produced congenic lines of C57BL/6 background that substituted regions around D17Mit119 with MSM-derived ones, and examined auditory brainstem response (ABR) thresholds for their hearing capacity at 6 and 12months of age. Three congenic lines carrying the approximately 14-Mb region between D17Mit274 and D17Mit183 retained normal hearing at 12months of age whereas two congenic lines not carrying this region tended to lose hearing at that age. We also investigated noise-induced hearing loss (NIHL) in congenic lines at 1, 7 and 14days after exposure to the noise of 100dB for 1h. Most congenic mice carrying the 14-Mb region did not exhibit permanent threshold shift (PTS) whereas mice not carrying this region exhibited a strong tendency of PTS, indicating the role of Ahl3 in susceptibility to NIHL. These results indicate that Ahl3 exists within the 14-Mb region and affects not only AHL but also NIHL.

Prevalence of gastric cancer decreases with age in long-living elderly in Japan, possibly due to changes in Helicobacter pylori infection status.

OBJECTIVES: The prevalence of Helicobacter pylori (Hp) infection and the development of gastric cancer are both believed to increase with age in Japan. However, no studies have investigated people older than 65 years in detail. In this study, we investigated the prevalence of Hp infection and gastric cancer in the elderly, and analyzed the influence of both factors on longevity. METHODS: All patients investigated were 65 years old and over. A total of 1877 autopsy cases were used to investigate the prevalence of gastric cancer and colonic cancer. Serum samples were obtained from 644 patients with dyspepsia and analyzed for Hp-IgG antibodies. Of these 644 patients, 63 underwent upper gastrointestinal endoscopies. Five biopsies were obtained and evaluated for the following morphological variables: neutrophils, mononuclear cell, atrophy, and intestinal metaplasia. Hp infection was evaluated histologically and with the (13)C-urea breath test. RESULTS: The prevalence of gastric cancer was significantly lower in subjects older than 85 years. The positive rate of serum Hp-IgG, and Hp infection as detected histologically and by the (13)C-urea breath test, also decreased with age. In Hp(+) patients, the neutrophil score significantly decreased with age. In Hp(-) patients, however, the intestinal metaplasia score significantly increased with age. CONCLUSIONS: The non-infection of Hp itself is not related to longevity in Japanese elderly, because even Hp(-) patients appear to have been infected previously with Hp. The lower prevalence of gastric cancer in the elderly may be due to the disappearance of Hp colonization, which may contribute to longevity in Japanese elderly.

Intrahepatic biliary papilloma morphologically similar to biliary cystadenoma.

A 37-year-old man presented complaining of epigastralgia. Abdominal ultrasonography revealed the presence of a papillary tumor (9 mm in diameter) in the cystic lesion (18 mm in diameter) in hepatic segment 4, which was accompanied by mild intrahepatic bile duct dilatation. Although abdominal computed tomography also showed the cystic lesion, it did not show papillary tumors inside the lesion. Endoscopic retrograde cholangiography showed the communication between the cystic lesion and the left hepatic duct. In addition, mucus was observed in the common bile duct. When transpapillary intraductal ultrasonography was performed through the left hepatic duct using a fine ultrasonic probe, a hyperechoic papillary and lobulated tumor was clearly shown in the cystic lesion. The wall of the cyst was smooth and there was no sign of tumor infiltration. Based on these findings, biliary cystadenoma was diagnosed and an extended left lobectomy was carried out. However, pathological findings postoperatively revealed that the lesion was a localized biliary papilloma, developing and extending to the intrahepatic duct. This case is rare and there have been no published reports describing a biliary papilloma morphologically similar to biliary cystadenoma.

Clinical differences between primary sclerosing cholangitis and sclerosing cholangitis with autoimmune pancreatitis.

OBJECTIVES: Sclerosing cholangitis (SC) with autoimmune pancreatitis (AIP) is similar to primary sclerosing cholangitis (PSC) with regard to cholangiographic findings, but only the former responds well to steroid therapy. This report concentrates on the clinical differences between these diseases. METHODS: The presenting complaint or abnormality, associated disease, cholangiographic findings, pancreatic changes, treatment, and clinical course were studied for several cases of PSC (n = 27) and SC with AIP (n = 20). RESULTS: SC with AIP as a diagnosis occurs abruptly with obstructive jaundice compared with PSC where diagnosis is often based on findings of asymptomatic liver test abnormalities. In addition, inflammatory bowel disease is only associated with PSC. The most prominent features of cholangiograms for the SC with AIP cases were stenosis of the lower common bile duct. However, sclerosing changes in the intra- and extrahepatic bile ducts or hilar hepatic region were observed for half of the cases. Only PSC showed stage III or IV liver biopsy findings. IgG4 was significantly higher in SC with AIP. CONCLUSIONS: SC with AIP and PSC are different clinical entities.

Combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker synergistically suppresses chronic pancreatitis in rats.

We recently demonstrated that both lisinopril and candesartan, an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker, respectively, attenuate pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori (WBN/Kob) rats. The purpose of the present study was to assess whether combination therapy with low doses of both, ineffective when given alone, might synergistically exert protective effects. Lisinopril, candesartan, or a combination of both in drinking water was administered to 10-week-old male WBN/Kob rats for 10 weeks. Parameters of inflammation and fibrosis, positive immunostaining for alpha-smooth muscle actin, and gene expression of cytokine and growth factors were assessed, as well as circulating renin-angiotensin system components. Dose-dependent effects of combination therapy were also investigated. Only combination therapy attenuated gross alterations in the pancreas, as quantitatively confirmed by increases in pancreatic weights and decreases in myeloperoxidase activity, hydroxyproline content, histologic scores, relative fibrosis area, and relative area of alpha-smooth muscle actin-positive cells. Combination therapy suppressed up-regulation of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 mRNA in the pancreas. Dose dependence of combination therapy was recognized with reference to improvement in these parameters. The conclusions are that combination therapy synergistically alleviated pancreatic inflammation and fibrosis in male WBN/Kob rats. This effect may be related to suppression of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 mRNA. Compared with the either therapy alone, combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor blocker may be more beneficial for treating chronic pancreatitis.

Evaluation of early gastric mucosal permeability induced by central thyrotropin-releasing hormone administration.

Accumulating evidence suggests that central thyrotropin-releasing hormone (TRH) administration induces gastric erosion 4 h after administration through the vagal nerves. However, early changes in the gastric mucosa during these 4 h have not been described. To assess early changes in the gastric mucosa after intracisternal injection of a stable TRH analog, pGlu-His-(3,3'-dimethyl)-ProNH2 (RX-77368), we measured the blood-to-lumen 51Cr-labeled EDTA clearance and examined the effects of vagotomy, atropine, omeprazole, and hydrochloric acid (HCl) on RX-77368-induced mucosal permeability. A cytoprotective dose of RX-77368 (1.5 ng) did not increase mucosal permeability. However, higher doses significantly increased mucosal permeability. Permeability peaked within 20 min and gradually returned to control levels in response to a 15-ng dose (submaximal dose). Increased mucosal permeability was not recovered after a 150-ng dose (ulcerogenic dose). This increase in permeability was inhibited by vagotomy or atropine. Intragastric perfusion with HCl did not change the RX-77368 (15 ng)-induced increase in permeability, but completely inhibited the recovery of permeability after the peak. Pretreatment with omeprazole did not change the RX-77368 (15 ng)-induced increase in permeability, but quickened the recovery of permeability after the peak. These data indicate that the RX-77368-induced increase in permeability is mediated via the vagal-cholinergic pathway and is not a secondary change in RX-77368-induced acid secretion. Inhibited recovery of permeability on exposure to an ulcerogenic RX-77368 dose or on exposure to HCl plus a submaximal dose of RX-77368 may be crucial for the induction of gastric mucosal lesions by central RX-77368 administration.

IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells.

Interleukin-8 (IL-8) has been reported to promote tumor cell growth in colon cancer cells after binding to its receptors, which are members of the G-protein coupled receptor (GPCR) family. Recent studies demonstrated that stimulation of GPCR can induce shedding of epidermal growth factor (EGF) ligands via activation of a disintegrin and metalloprotease (ADAM), with subsequent transactivation of the EGF receptor (EGFR). In this study, we investigated mechanisms of cell proliferation and migration stimulated by IL-8 in a human colon carcinoma cell line (Caco2). IL-8 increased DNA synthesis of Caco2 in a dose dependent manner and this was inhibited by ADAM, EGFR kinase, and MEK inhibitors. IL-8 transiently induced EGFR tyrosine phosphorylation after 5-90 min and this was completely inhibited by ADAM inhibitor. Neutralizing antibody against HB-EGF as a key ligand for EGFR also blocked transactivation of EGFR and cell proliferation by IL-8. Since IL-8-induced cell migration was further suppressed by the ADAM inhibitor and the HB-EGF neutralizing antibody, our data indicate that IL-8 induces cell proliferation and migration by an ADAM-dependent pathway, and that HB-EGF plays an important role as the major ligand for this pathway.

Cytoarchitecture of the normal rat olfactory epithelium: light and scanning electron microscopic studies.

The three-dimensional cytoarchitecture of the normal rat olfactory epithelium was examined by scanning electron microscopy (SEM) of KOH digested tissues as well as by light and transmission electron microscopy of plastic sections. Observations specimens from the lateral side of the olfactory epithelium allowed identification of four cell types by their surface structure: olfactory neurons, supporting cells, basal cells, and duct cells of the Bowman's gland. The olfactory neurons were characterized by the presence of a thick apical process (i.e., dendrite) and a thin basal process (i.e., axon). These olfactory neurons tended to be aligned along the vertical axis of the epithelium. Immature olfactory neurons were present at the basal part of the epithelium and had a pear-shaped cell body with a thin and long axon and a short dendrite which failed to reach the epithelial surface. Supporting cells were roughly columnar in shape and occupied the full length of the epithelium. They became thinner in the basal two thirds of their length but had branched foot processes spreading on the basal surface of the epithelium. Basal cells located in the basal epithelial region were oval, round or cuboidal and present among the foot processes of the supporting cells. The ducts of the Bowman's gland entered the epithelium from the lamina propria and took straight, perpendicular courses within the epithelium. These intraepithelial ducts were composed of several slender cells. The acinar cells are sometimes present in the epithelium and appeared as a globular bulge of the duct at the basal part of the epithelium. SEM observation of the basal surface of the olfactory epithelium also clearly showed that axon bundles were surrounded by the sheet-like processes of Schwann cells, the investment being found at the base of the epithelium just before axon bundles leave the epithelium.