A chronic toxicity study of diphenylarsinic acid in F344 rats in drinking water for 52 weeks

Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. The purpose of the present study was to evaluate the potential toxicity of DPAA when administered to rats in their drinking water for 52 weeks. DPAA was administered to groups 1–4 at concentrations of 0, 5, 10, and 20 ppm in their drinking water for 52 weeks. There were no significant differences in the final body weights between the control groups and the treatment groups in male or female rats. In serum biochemistry, in females 20 ppm DPAA significantly increased alkaline phosphatase and γ-glitamyl transferase compared to controls, and 10 and 20 ppm DPAA significantly increased total cholesterol compared to controls. Absolute and relative liver weights were significantly increased in females treated with 20 ppm DPAA compared to the control group. Dilation of the common bile duct outside the papilla of Vater and stenosis of the papilla of Vater was observed in all male and female rats administered 20 ppm DPAA. The incidence of intrahepatic bile duct hyperplasia was significantly increased in male and female rats treated with 20 ppm DPAA compared to the control groups. These results suggest that DPAA is toxic to the bile duct epithelium in rats. The no-observed adverse effect levels of DPAA were estimated to be 10 ppm (0.48 mg/kg b.w./day) for males and 5 ppm (0.35 mg/kg b.w./day) for females under the conditions of this study.     

Serological Assays Based on Recombinant Viral Proteins for the Diagnosis of Arenavirus Hemorrhagic Fevers

The family Arenaviridae, genus Arenavirus, consists of two phylogenetically independent groups: Old World (OW) and New World (NW) complexes. The Lassa and Lujo viruses in the OW complex and the Guanarito, Junin, Machupo, Sabia, and Chapare viruses in the NW complex cause viral hemorrhagic fever (VHF) in humans, leading to serious public health concerns. These viruses are also considered potential bioterrorism agents. Therefore, it is of great importance to detect these pathogens rapidly and specifically in order to minimize the risk and scale of arenavirus outbreaks. However, these arenaviruses are classified as BSL-4 pathogens, thus making it difficult to develop diagnostic techniques for these virus infections in institutes without BSL-4 facilities. To overcome these difficulties, antibody detection systems in the form of an enzyme-linked immunosorbent assay (ELISA) and an indirect immunofluorescence assay were developed using recombinant nucleoproteins (rNPs) derived from these viruses. Furthermore, several antigen-detection assays were developed. For example, novel monoclonal antibodies (mAbs) to the rNPs of Lassa and Junin viruses were generated. Sandwich antigen-capture (Ag-capture) ELISAs using these mAbs as capture antibodies were developed and confirmed to be sensitive and specific for detecting the respective arenavirus NPs. These rNP-based assays were proposed to be useful not only for an etiological diagnosis of VHFs, but also for seroepidemiological studies on VHFs. We recently developed arenavirus neutralization assays using vesicular stomatitis virus (VSV)-based pseudotypes bearing arenavirus recombinant glycoproteins. The goal of this article is to review the recent advances in developing laboratory diagnostic assays based on recombinant viral proteins for the diagnosis of VHFs and epidemiological studies on the VHFs caused by arenaviruses.     

Prevalence and viral DNA loads of three novel human polyomaviruses in skin cancers from Japanese patients

Merkel cell polyomavirus (MCPyV), human polyomaviruses 6 (HPyV6) and 7 (HPyV7) are novel human polyomaviruses. This study investigated their detection rates and DNA loads in various skin cancers from Japanese patients. MCPyV, HPyV6 and HPyV7 were detected in 22.2%, 3.2% and 1.6% of squamous cell carcinomas, 18.0%, 2.0% and 4.0% of basal cell carcinomas, and 19.1%, 4.3% and 4.3% of melanomas, respectively. Quantitative real‐time polymerase chain reaction showed that their DNA loads were low. These findings provide the first evidence of the prevalence of HPyV6 and HPyV7 in skin cancers in Asia. Nucleotide differences were found in the large T‐sequenced region between Japanese and North American isolates: a nucleotide substitution of A to G for HPyV6; and a nucleotide substitution of T to C and the insertion of a gap for HPyV7. This suggested that two genotypes of HPyV6 and HPyV7 would be present and associated with geographical origin.     

Acute hepatitis B in Japan: Incidence,clinical practices and health policy

Aim: The epidemiology of acute hepatitis B is unknown in many countries, and the clinical features of this disease remain unclear. In this study, we used the Diagnosis Procedure Combination (DPC) database to estimate the incidence of acute hepatitis B and investigate the clinical practices for acute hepatitis B in Japan. Methods: The DPC database is a nationwide discharge abstract and administrative claims database, covering 40% of all inpatient admissions to acute care hospitals between 1 July and 31 December each year in Japan. We identified cases with a diagnosis of acute hepatitis B between 2007 and 2008. Patient characteristics, length of stay, in‐hospital mortality and total charges were determined. Clinical practice patterns were examined, including drugs used and procedures performed during hospitalization. Results: We identified 890 cases with acute hepatitis B among 5.85 million inpatients in the database. The mean age was 40.0 years old and 76% were male. The incidence of acute hepatitis B was estimated to be approximately 2100–2400/year (17–19/1 million people per year). Of 890 cases, 53 (6.0%) developed fulminant hepatitis and 36 (4.0%) died. Nucleos(t)ide analogs were prescribed for 226 cases (25.4%). Only 194 cases (21.8%) were tested for HIV status. Conclusion: It is essential to monitor the trends of this communicable and preventable disease. The establishment and distribution of appropriate clinical evidence and guidelines are vital to improve the clinical practices for acute hepatitis B.     

Changes of NK Cells in Preeclampsia

The regulation of uterine and circulating peripheral blood natural killer (NK) cells has been associated with reproductive immunology such as recurrent pregnancy losses, implantation failures, or preeclampsia. Preeclampsia is a hypertensive disorder of pregnancy characterized by increased blood pressure accompanied by proteinuria and is a major cause of maternal and fetal mortality. Natural cytotoxicity receptors (NCRs) are unique markers, which regulate NK cell cytotoxicity and cytokine production. The relation of NCRs to reproduction is not fully characterized yet. The different profile of NCRs expression may suggest presence of abnormal regulation of NK cell in women with reproductive failures. Pregnant women with preeclampsia carry immunological abnormalities of NCRs on peripheral blood NK cells during pregnancy. The lower expression of NKp46⁺ NK cells in women with preeclampsia may account for the higher production of NK1 cytokine that is known as NK1 shift in pregnant women with preeclampsia. Evaluation of NKp46 on peripheral blood NK cells may be applicable to find the onset of preeclampsia. In this review, various expressions of NK cell surface markers including NCRs on NK cells, NK cell cytotoxicity, and production of cytokines and angiogenic factors by NK cells were reviewed in relation to preeclampsia.     

Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre,multinational study using virtual microscopy

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M
(2012) Histopathology  61, 562–575 Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy Aims: Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice. Methods and results: A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1‐3 cytokeratin‐immunostained, whole‐slide digital scans from 50 pT1–pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants’ experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding‐positive cases with all methods compared to H&E‐stained slides, but did not influence agreement levels. Conclusions: An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.