Diagnostic and predictive performance and standardized threshold of traditional biomarkers for drug‐induced liver injury in rats

Traditional biomarkers such as alanine and aspartate aminotransferase (ALT, AST) and total bilirubin (TBIL) have been widely used for detecting drug‐induced liver injury (DILI). Although the Food and Drug Administration (FDA) proposed standardized thresholds for human as Hy's law, those for animals have not been determined, and predictability of these biomarkers for future onset of hepatic lesions remains unclear. In this study, we investigated these diagnostic and predictive performance of 10 traditional biomarkers for liver injury by receiver‐operating characteristic (ROC) curve, using a free‐access database where 142 hepatotoxic or non‐hepatotoxic compounds were administrated to male rats (n = 5253). Standardization of each biomarker value was achieved by calculating the ratio to control mean value, and the thresholds were determined under the condition of permitting 5% false positive. Of these 10 biomarkers, AST showed the best diagnostic performance. Furthermore, ALT and TBIL also showed high performance under the situation of hepatocellular necrosis and bile duct injury, respectively. Additionally, the availability of the diagnostic thresholds in difference testing facility was confirmed by the application of these thresholds to in‐house prepared dataset. Meanwhile, incorrect diagnosis by the thresholds was also observed. Regarding prediction, all 10 biomarkers showed insufficient performance for future onset of hepatic lesions. In conclusion, the standardized diagnostic thresholds enable consistent evaluation of traditional biomarkers among different facilities, whereas it was suggested that novel biomarker is required for more accurate diagnosis and prediction of DILI. Copyright © 2014 John Wiley & Sons, Ltd.     

The linkage among ambulance transports,death and climate parameters in Asahikawa City,Japan

Objective

The aim of this study was to investigate the linkage among climate parameters, total ambulance transports and the number of deaths in Asahikawa City in northern Japan.

Methods

Monthly data on total ambulance transports and the number of deaths from January 2004 to December 2011 were obtained from Asahikawa City Fire Department and the Asahikawa City official website. Climate parameters for the required period were also obtained from the Japan Meteorological Agency, Japan. To adjust for the population, we also used monthly population data on Asahikawa City. The linkage among climate parameters, total ambulance transports and the number of deaths was evaluated by ecological analysis.

Results

The mean air temperature in the Asahikawa area was 7.3 ± 10.1 °C. Total ambulance transports (/a hundred thousand people/day) and the number of deaths (/a hundred thousand people/day) were 10.0 ± 0.6 and 2.6 ± 0.3, respectively. Using quadratic curves, total ambulance transports and the number of deaths were weakly correlated with some climate parameters. The number of deaths was weakly and positively correlated with total ambulance transports.

Conclusion

A weak linkage among climate parameters, total ambulance transports and the number of deaths was noted in Asahikawa City, Japan. However, these associations were not as high as expected.     

Early Detection of High-grade Biliary Intraepithelial Neoplasia (BilIN-3) in the Cystic Duct Visualized by SpyGlass DS Cholangioscopy

An 84-year-old man was admitted with epigastralgia. Computed tomography showed contrast-enhanced wall thickness in the cystic duct. An endoscopic examination revealed short irregular stricture in the cystic duct, and per-oral cholangioscopy revealed a reddish papillary tumor at the stricture site. Surgical resection revealed high-grade biliary intraepithelial neoplasia (BilIN) at the stricture site of the cystic duct. To our knowledge, this is the first case of a solitary high-grade BilIN epithelium in the cystic duct detected by per-oral cholangioscopy.     

Outcome of the Sauvé–Kapandji procedure for distal radioulnar joint disorder with rheumatoid arthritis or osteoarthritis: Results of one-year follow-up

Objectives: We performed the Sauvé–Kapandji procedure for treating disorders of the distal radioulnar joint (DRUJ) in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). This study aimed to compare and clarify the results of the SK procedure between RA and OA patients. We report the one-year follow-up results of patients who underwent the SK procedure to correct the DRUJ disorder caused by RA or OA.

Methods: The study included 22 wrists of 19 patients with RA and 10 wrists of nine patients with OA. Pain, grip strength and range of motion of the wrist were examined clinically. For the evaluation of the stability of the carpus, ulnar stump and bone union, parameters were measured using radiographs. Shortened disabilities of the arm, shoulder and hand questionnaire (QuickDASH) was used for functional evaluation.

Results: Wrist pain reduced in all cases, and bone union was achieved in all wrists. The QuickDASH score significantly improved in both patients with RA and OA. In patients with RA, the range of motion increased significantly with regard to supination but decreased significantly with regard to palmar flexion. Carpal alignment and ulnar stump stability were maintained well at one-year follow-up.

Conclusion: The Sauvé–Kapandji procedure for treating disorders of the distal radioulnar joint DRUJ showed good results clinically and radiographically, irrespective of RA or OA.     

Comparative inhibitory effects of cilostazol and ticlopidine on subacute stent thrombosis and platelet function in acute myocardial infarction patients with percutaneous coronary intervention

We compared the effects of ticlopidine and cilostazol on the prevention of subacute stent thrombosis (SAT) in acute myocardial infarction (AMI) patients with stenting. We also analyzed the cause of the difference by measuring platelet aggregation activity. Consecutive patients who underwent successful stenting for AMI between March 2001 and March 2004 were analyzed. In addition to aspirin (100 mg/day), cilostazol (200 mg/day) was administered to 99 cases between March 2001 and May 2002 and ticlopidine (200 mg/day) was administered to 85 cases between June 2002 and February 2004. The incidence of SAT within four weeks after stenting was analyzed. Thirty-eight AMI patients were randomized and their platelet aggregation activity was measured using a laser-scattered aggregometer (18 cases in the cilostazol group and 20 cases in the ticlopidine group). SAT did not occur in the ticlopidine group while 5 cases (5.1%) of SAT occurred in the cilostazol group (P < 0.05). The inhibitory activity of cilostazol for ADP-induced platelet aggregation was lower than that of ticlopidine (P < 0.05). Cilostazol with aspirin after stenting in AMI patients showed more frequent SAT than ticlopidine with aspirin. One of the causes for this difference was speculated to be the weaker inhibitory activity of cilostazol for ADP-induced platelet aggregation.     

Hepatocellular carcinoma with sarcomatous change arising in primary biliary cirrhosis

We report an autopsy case of hepatocellular carcinoma (HCC) with sarcomatous change arising in the context of primary biliary cirrhosis (PBC) in a 79-year-old man. Primary biliary cirrhosis was diagnosed (stage I according to Scheuer's classification) by findings on blood biochemical analysis, laparoscopy, and liver biopsy at age 69 years. Five years later, (at age 74 years), a mass lesion was detected in the S₆ region of the liver by abdominal ultrasonography, and target biopsy revealed well differentiated HCC. Blood biochemistry, ultrasonography, and computed tomography findings showed that the PBC had progressed to stage IV (cirrhotic stage). Percutaneous ethanol injection therapy (PEIT) was administered to the HCC several times over a 5-year period; however, the patient died of liver failure in February, 1994 (at age 79 years). Viral markers for hepatitis B and C were negative during the course, and hepatitis C virus RNA was not detected by polymerase chain reaction. Autopsy findings showed liver cirrhosis and diffuse involvement of spindle-shaped sarcomatoid cells in the liver, particularly in the S₆ region, associated with several nodules of trabecular HCC cells. A zone of transition between the sarcomatoid cells and the trabecular hepatocellular carcinoma cells was observed. The sarcomatoid cells were diffusely disseminated in the peritoneal cavity and had metastasized to multiple organs. Immunohistochemically, the cells were positive for fibrinogen, as were the coexisting trabecular hepatocellular carcinoma cells. The HCC had been treated several times with PEIT. Of interest, PEIT may be an important factor in this type of tumor progression.     

Detection of BCL2-IGH rearrangement on paraffin-embedded tissue sections obtained from a small submucosal tumor of the rectum in a patient with recurrent follicular lymphoma

A 59-year-old woman was admitted to our hospital because of recurrent follicular lymphorna (FL). Colonoscopic examination revealed a rectal submucosal tumor (SMT) without any erosions and ulcers. In this patient, it was difficult to distinguish non-Hodgkin‘s lymphoma (NHL) invasion from other disorders of the colon including carcinoid tumor merely based on endoscopic findings. Histopathologic and immunohistochemical studies on biopsy specimens showed an infiltration of atypical lymphocytes that were positive for CD20 and BCL2 but negative for UCHL-1. Fluorescence in situ hybridization on paraffin-embedded tissue sections (T-FISH) identified a translocation of BCL2 with IGHgene.Based on these findings, the tumor was defined as an invasion of FL. T-FISH method is useful for the detection of a monoclonality of atypical lymphocytes in an SMT of the gastrointestinal tract, and particularly for the detection of chromosomal translocations specific to lymphoma subtypes.     

Intrinsic GABAergic system of adrenal chromaffin cells.

Histochemical and biochemical studies demonstrate that gamma-aminobutyric acid (GABA), glutamic acid decarboxylase (EC 4.1.1.15), and GABA aminotransferase (EC 2.6.1.19) are present in bovine adrenal chromaffin cells. Moreover, [3H]GABA can be taken up and stored by primary cultures of adrenal chromaffin cells. Nicotinic receptor stimulation or KCl depolarization releases the [3H]GABA taken up by these cell cultures. GABA and benzodiazepine recognition sites located in chromaffin cells interact with each other with modalities similar to those described for GABA and benzodiazepine recognition sites located in synaptic membranes prepared from brain tissue. Bicuculline facilitates the release of catecholamine from chromaffin cells induced by nicotinic receptor stimulation but it fails to influence the release of catecholamine evoked by K+ depolarization. Since the GABA-benzodiazepine receptor system appears to modulate nicotinic receptor function, it is suggested that GABA transmission might participate in modulating responsiveness of chromaffin cells to incoming cholinergic stimuli.