Development of hepatocellular carcinoma following treatment with6-mercaptopurine for ulcerative colitis: investigation of chromosomal aberration by comparative genomic hybridization

In a 64-year-old man who had been treated with prednisolone (PSL) and 6-mercaptopurine (6MP) for a long period, for ulcerative colitis (UC), hepatocellular carcinoma (HCC) was detected incidentally. The UC was in remission with these medications. After he had been taking these medications for about 8 years, HCC was detected by computed tomography (CT), done for the evaluation of an other disease. Blood chemistry examination results were normal, except that the protein induced by vitamin K antagonist (PIVKA)-II level was 7940 AU/ml. We performed resection of liver segment V. With comparative genomic hybridization, chromosomal aberrations were recognized; these were gains of 1q, 3ptel-21, 8p12, and 22q11.23–22q13.1. Generally, HCC is associated with hepatitis virus infection in most cases, but in this patient, the HCC was not related to hepatitis C virus (HCV) or HBV. It is presumed that this case was related to the immunosuppressive therapy for UC and was associated with the gains of 1q, 3p, and 8p.     

Correlation between expression of orotate phosphoribosyl transferase and 5-fluorouracil sensitivity, as measured by apoptosis index in colorectal cancer tissue

Background. 5-Fluorouracil remains a key drug in the treatment of colorectal cancer, and the development of a simple and effective test for selecting patients likely to benefit from postoperative adjuvant chemotherapy is an important objective. Aim of the Study. This study aimed to clarify the feasibility of measuring apoptotic cell rate (AI%) in tumor after short-term oral 5-fluorouracil administration prior to surgery with the objective of establishing a simpler method to test for sensitivity. Methods. Forty-five colorectal cancer patients were allocated to two groups, and 21 patients were given oral 5-FU for 3 d prior to surgery. The AI% in surgical specimen, detected by TUNEL staining, was compared in the 5-FU-loaded and control groups. The correlation of AI% with 5-FU metabolic enzyme mRNA levels in tumor was also evaluated. Results. The AI% was significantly higher in the tumor tissue of patients receiving 5-FU than in the control group (p<0.0005). Although insignificant, thymidylate synthase mRNA level and orotate phosphoribosyl transferase mRNA demonstrated a weak positive correlation with AI%. Conclusions. The AI% measurement in tumor tissue following a 5-FU oral load for 3 d prior to surgery was feasible. It remains to be elucidated if this measurement as a new 5-FU sensitivity test reflects the prognosis with 5-FU-based postoperative adjuvant chemotherapy.     

Efficient drug delivery to atherosclerotic lesions and the antiatherosclerotic effect by dexamethasone incorporated into liposomes in atherogenic mice

In order to confirm the efficacy of dexamethasone (DXM) incorporated into liposomes (DXM-liposomes) on atherosclerosis, drug delivery to atherosclerotic lesions and the antiatherosclerotic effect by DXM-liposomes were investigated in atherogenic mice. DXM-liposomes were prepared with egg yolk phosphatidylcholine, cholesterol and dicetylphosphate in a lipid molar ratio of 7/2/1 by the hydration method and then adjusted to three different particle sizes to clarify the influence of particle size on the drug delivery to atherosclerotic lesions and the effect on atherosclerosis. The particle sizes of DXM-liposomes were 519 nm (L500), 202 nm (L200) and 68.6 nm (L70), respectively. In both size, DXM concentration and DXM/lipid molar ratio in DXM-liposomes suspension were 1 mg DXM/ml and 0.134 mol DXM/mol total lipids, respectively. Atherogenic mice used as an experimental model develop an atherosclerotic lesion in the aorta and they were prepared by feeding an atherogenic diet for 14 weeks. The aortic pharmacokinetics of DXM-liposomes was examined by intravenous administration to atherogenic mice. The aortic uptake clearance of DXM in atherogenic mice treated with L200 was 2.6--3.2 fold greater than that in animals treated with L500, L70 or free DXM (f-DXM). Furthermore, the effects of DXM-liposomes on atherosclerosis were examined by intravenous administration to atherogenic mice once a week from 8 to 14 weeks. The antiatherosclerotic effects of DXM-liposomes were evaluated by determination of the aortic cholesterol ester (CE) level. The aortic CE level in atherogenic mice treated with L200 (55 microg DXM/kg) was significantly lower than that in animals treated with PBS. The antiatherosclerotic effect of L200 (55 microg DXM/kg) was significantly more potent than that of f-DXM (550 microg DXM/kg). These findings suggest that efficient delivery of DXM to the atherosclerotic lesions by L200 induces an excellent antiatherosclerotic effect at a lower dose. Therefore, L200 may be useful in the development of drug delivery systems for atherosclerotic therapy.     

Effect of etidronate on aortic calcification and bone metabolism in calcitriol-treated rats with subtotal nephrectomy

The present study was undertaken to determine the effects of etidronate (ED) on calcitriol-induced aortic calcification and bone metabolism in rats with renal failure. Severe aortic calcification was induced by treatment with calcitriol for 3 weeks in rats in which 5/6 of the kidneys were removed (SNx group). Treatment of ED (10 mg/kg) together with calcitriol after subtotal nephrectomy (SNx) significantly inhibited thoracic and abdominal aortic calcification 3 weeks after the operation; however, ED (2 mg/kg) was ineffective. The serum levels of osteocalcin and pyridinoline decreased in ED (10 mg/kg) treated-renal failure rats compared with SNx rats. Total bone mineral density (BMD) in the SNx group was lower than that in the sham group, in which animals were treated with calcitriol after a sham operation. The total BMD value in the ED (10 mg/kg)-treated group was similar to that in the SNx group, whereas the levels of cancellous BMD were low in the ED (10 mg/kg)-treated rats. Our data show that ED at a dosage that suppresses bone metabolism markedly inhibits vascular calcification in rats with renal failure.     

Symptomatological structure of volatile solvent-induced psychosis: is "solvent psychosis" a discernible syndrome?

Solvent-induced psychosis has been clinically identified among patients suffering from dependence on volatile solvents and those in psychotic state due to chronic solvent use. To clarify the symptomatological difference between solvent-induced psychosis and schizophrenia, the principal component analysis with VARIMAX rotation was applied to the point and duration estimates of symptoms observed among the solvent group and among the schizophrenic group. There were no significant group differences in age and family history of any psychosis. The study findings are as follows: (1) It is difficult to distinguish two groups based on the prevalence rates of symptoms alone. (2) However, the principal component VARIMAX rotation analysis of the prevalence and duration observing among the solvent group revealed seven factors consisting of "amotivation", "intoxication", "emotional instability", "delusion", "hallucination", "disinhibition" and "memory". The seven factors explained 75.4% of the variance of the symptoms in this group. (3) The same analysis applied to the data from the schizophrenic group showed six factors consisting of "thought progression", "emotional instability", "amotivation (or negative symptoms)", "delusion", "hallucination" and "anxiety". These factors explained 62.9% of the variance in the data of the schizophrenic group. These results support clinical observations the "amotivational syndrome" may be a characteristic feature of patients suffering from solvent-induced psychosis. The results also suggest "solvent psychosis" is a discernible syndrome, and is distinctive from psychotic symptoms of typical schizophrenia.     

QT PRODACT: in vivo QT assay in anesthetized dog for detecting the potential for QT interval prolongation by human pharmaceuticals

The purpose of this study was to assess the utility of the isoflurane-anesthetized dog model for detecting the potential for QT interval prolongation by human pharmaceuticals. The effects of 10 positive compounds with torsadogenic potential, 8 negative compounds with little torsadogenic potential, and dl-sotalol as a common positive compound were evaluated in 5 facilities in accordance with the common protocol approved by QT PRODACT. Each test compound was cumulatively infused into male beagle dogs anesthetized with isoflurane. Surface lead II ECG, blood pressure, and plasma concentrations for the positive compounds were measured. Repeated administration of the vehicle examined in each facility before the start of the experiments resulted in a slight, but not significant, change in corrected QT (QTc) interval, indicating that this model only shows slight experimental variation. Although an inter-facility variability in the extent of dl-sotalol-induced QT interval prolongation was observed, dl-sotalol significantly prolonged QTc interval in all facilities. All positive compounds significantly prolonged QTc interval at plasma levels up to 10 times those in patients who developed prolonged QTc interval or TdP, whereas no negative compounds did so. These data suggest that the in vivo QT assay using the anesthetized dog is a useful model for detecting the potential for QT interval prolongation by human pharmaceuticals.     

Estimation of detection limit from slope of B/B0 in competitive ELISA

A method has been proposed for determining the detection limit (L(D)) from the slope of a semilogarithmic plot of a B/B(0) curve in competitive enzyme linked immunosorbent assay (ELISA). As an application, this paper describes a graphic determination of L(D) from analogue data in the literature. The L(D) obtained corresponds to the concentration at which the relative standard deviation of concentration estimates is 30%.     

Cigarette smoke activates human monocytes by an oxidant-AP-1 signaling pathway: implications for steroid resistance

Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smoking-induced pathophysiology is often resistant to the anti-inflammatory effects of glucocorticoids. The nature of cigarette smoke-induced inflammation is still not defined, although neutrophil recruitment and activation seem to be consistent features. In the current study, we have used a range of approaches to demonstrate that cigarette smoke activates human monocytes and macrophages to release the CXC chemokine CXCL8 [(interleukin-8 (IL-8)]. Furthermore, we show for the first time that cigarette smoke synergizes with proinflammatory cytokines IL-1beta and tumor necrosis factor-alpha, and it is this interaction that confers steroid resistance to smoke-induced CXCL8 release. We go on to show that smoke-induced activation of human cells is an oxidant-mediated phenomenon acting through activator protein-1, but not nuclear factor kappaB, pathway. These observations add significantly to our understanding of smoke as an inflammatory stimulus that has implications for potential the development of treatments of smoking or related disease.     

Adenovirus-mediated interferon alpha gene transfer induces regional direct cytotoxicity and possible systemic immunity against pancreatic cancer

We previously demonstrated a characteristically high sensitivity of pancreatic cancer cells to interferon alpha (IFN-alpha) gene transfer, which induced a more prominent growth suppression and cell death in pancreatic cancer cells than in other types of cancers and normal cells. The IFN-alpha protein can exhibit both direct cytotoxicity and indirect immunological antitumour activity. Here, we dissected and examined the two mechanisms, taking advantage of the fact that IFN-alpha did not show any cross-species activity in its in vivo effect. When a human IFN-alpha adenovirus was injected into subcutaneous xenografts of human pancreatic cancer cells in nude mice, tumour growth was significantly suppressed due to cell death in an adenoviral dose-dependent manner. The IFN-alpha protein concentration was markedly increased in the injected subcutaneous tumour, but leakage of the potent cytokine into the systemic blood circulation was minimal. When a mouse IFN-alpha adenovirus was injected into the same subcutaneous tumour system, all mice showed significant tumour inhibition, an effect that was dependent on the indirect antitumour activities of IFN-alpha, notably a stimulation of natural killer cells. Moreover, in this case, tumour regression was observed not only for the injected subcutaneous tumours but also for the untreated tumours at distant sites. This study suggested that a local IFN-alpha gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its dual mechanisms of antitumour activities and lack of significant toxicity.