Carcinogenicity of biphenyl in mice by two years feeding

Carcinogenicity and chronic toxicity of biphenyl was examined in the male and female BDF1 mice fed a diet containing biphenyl at 667, 2,000 or 6,000 ppm for 2 years. There was no difference in survival rate between any biphenyl-containing diet-fed group of either sex and the respective control. Body weights of the males and females fed 6,000 ppm diet were significantly lower than the respective control. Incidences of hepatocellular carcinomas and hepatocellular adenomas in the females fed diets containing biphenyl were significantly increased in a dose-related manner, and exceeded a range of the historical control data in the Japan Bioassay Research Center. Incidences of basophilic cell foci in the liver were increased in the females fed 2,000 and 6,000 ppm diets. There was no increase in tumor or tumor-related lesion in the males fed diets containing biphenyl. Chronic toxicity of biphenyl was characterized by increased incidences of urothelial desquamation in the renal pelvis in males and females and mineralization in the inner stripe of renal outer medulla in females, as well as changes in serum levels of BUN, ALP and some electrolytes in males and females. In conclusion, the 2-year oral administration of biphenyl-containing diets induced pre-neoplastic and neoplastic lesions in the liver of females and non-neoplastic lesions in the kidney of males and females. Causative factors for the biphenyl-induced hepatocarcinogenicity were discussed in light of our published finding of peroxisome proliferation.     

Spontaneous Harderian Gland Adenocarcinoma in a Female F344 Rat: A Case Report

Harderian gland tumors are extremely rare in female F344 rats. An expansive enlarging lesion of the Harderian gland with compression, distortion and invasion of the surrounding muscle was found in a 110-week-old female F344/DuCrj rat, which was diagnosed as a Harderian gland adenocarcinoma. Epithelial growth patterns such as glandular, lobular, papillary and duct forming patterns were exhibited in most areas of the tumor. The tumor cells were pleomorphic and atypical. In one part of the tumor, poorly differentiated areas were found. This case was observed in the middle dose group of a carcinogenicity study of diphenylamine, which was not carcinogenic, we determine to be this case was a spontaneous tumor.     

Consensus-based reporting standards for diagnostic test accuracy studies for paratuberculosis in ruminants

The Standards for Reporting of Diagnostic Accuracy (STARD) statement (www.stard-statement.org) was developed to encourage complete and transparent reporting of key elements of test accuracy studies in human medicine. The statement was motivated by widespread evidence of bias in test accuracy studies and the finding that incomplete or absent reporting of items in the STARD checklist was associated with overly optimistic estimates of test performance characteristics. Although STARD principles apply broadly, specific guidelines do not exist to account for unique considerations in livestock studies such as herd tests, potential use of experimental challenge studies, a more diverse group of testing purposes and sampling designs, and the widespread lack of an ante-mortem reference standard with high sensitivity and specificity. The objective of the present study was to develop a modified version of STARD relevant to paratuberculosis (Johne's disease) in ruminants. Examples and elaborations for each of the 25 items were developed by a panel of experts using a consensus-based approach to explain the items and underlying concepts. The new guidelines, termed STRADAS-paraTB (Standards for Reporting of Animal Diagnostic Accuracy Studies for paratuberculosis), should facilitate improved quality of reporting of the design, conduct and results of paratuberculosis test accuracy studies which were identified as "poor" in a review published in 2008 in Veterinary Microbiology.     

An automated anion-exchange chromatographic procedure for the estimation of saccharides in acid hydrolysates of soil

It is well known that the major neutral monosaccharide components released from soil by acid hydrolysis are glucose, galactose, mannose, arabinose, xylose, ribose, rhamnose and fucose. A colorimetric determination of the saccharide mixture released from soil is unsatisfactory for determining an accurate figure for soil saccharides. More precise information can be obtained by the determination of monosaccharides after separation by chromatography. Paper and thin-layer chromatography for quantitative analysis are rather time consuming and laborious. The gas chromatographic procedure was applied successfully for the analysis of sugars in soil hydrolysates by OADES et at. (7). Preparation of the various derivatives for gas chromatography still requires many steps, much handling of the sample, and considerable time, although final analysis of the product derivative is accomplished in an hour or two.     

Mechanism-based CYP2D6 inactivation by acridone alkaloids of Indonesian medicinal plant Lunasia amara

Fourteen acridone alkaloids isolated from Lunasia amara Blanco were tested for their mechanism-based inhibition on human liver microsomal dextromethorphan O-demethylation activity, a prototype marker for cytochrome P450 2D6 (CYP2D6). Among the 14 compounds, 5-hydroxygraveroline (1), 8-methoxyifflaiamine (2), lunamarine (3), and lunine (12) increased their inhibitory activity with increasing preincubation time. Then, we further examined the possibility of mechanism-based inhibition on 5-hydroxygraveroline (1) and lunamarine (3), which showed the potent inhibition. Further investigations on 1 and 3 showed that the characteristic time- and concentration-dependent inhibition, which required a catalytic step with NADPH, was not protected by nucleophiles, and was decreased by the presence of a competitive inhibitor. Thus, 1 and 3 were concluded as mechanism-based inactivators of CYP2D6.     

A simple preparation of betulinic acid from sycamore bark

Betulinic acid is a biologically active compound, which has been well-known for anti-cancerous properties especially for skin. Recently, it has been drawn attention as a compound for combating AIDS. It can be chemically derived from betulin or by solvent extraction from bark. However, bark extracts are complex mixtures that always contain compounds with a wide spectrum of polarity. In this study, we have found a simple method to get high purity betulinic acid from Sycamore outer bark using hot water pre-treatment followed by hydrophilic organic solvent extraction with a yield of 5–6% (w/w).     

Agent-based model for Johne’s disease dynamics in a dairy herd

Johne’s disease is an infectious gastrointestinal disease in ruminants caused by Mycobacterium avium subsp. paratuberculosis that causes diarrhea, emaciation, decreased milk production and eventually death. The disease is transmitted in utero and via milk and colostrums to calves, and fecal-orally to all age classes. Financial losses due to the disease are estimated to be over $200 million in the US dairy industry. The goal of this study was to evaluate the cost effectiveness of control measures based on diagnosis with a sensitive ELISA, EVELISA. An agent-based, discrete time model was developed to simulate Johne’s disease dynamics in a US dairy herd. Spatial aspects of disease transmission were taken into account by using six spatial compartments. The effects on disease prevalence were studied with and without transmission routes included in the model. Further, using the model, cost effectiveness of ELISA-based Johne’s disease control was evaluated. Using the parameters we collected and assumed, our model showed the initial prevalence of Johne’s disease (33.1 ± 0.2%) in the farm increased to 87.7 ± 1.7% in a 10 year-simulation. When ELISA-based control measures were included in the simulation, the increase in prevalence was significantly slowed down, especially when EVELISA was used. However, the level of the prevalence was still higher than the initial level after 10 year simulation even with the ELISA-based diagnostic intervention. The prevalence was further reduced when quarterly ELISA testing was included. The cost analysis showed that the quarterly ELISA and EVELISA testing could bring $44.8 and $51.5/animal/year more revenues, respectively, to a dairy farm.

Electronic supplementary material

The online version of this article (doi:10.1186/s13567-015-0195-y) contains supplementary material, which is available to authorized users.     

An immuno-epidemiological model for Johne’s disease in cattle

To better understand the mechanisms involved in the dynamics of Johne’s disease in dairy cattle, this paper illustrates a novel way to link a within-host model for Mycobacterium avium ssp. paratuberculosis with an epidemiological model. The underlying variable in the within-host model is the time since infection. Two compartments, infected macrophages and T cells, of the within-host model feed into the epidemiological model through the direct transmission rate, disease-induced mortality rate, the vertical transmission rate, and the shedding of MAP into the environment. The epidemiological reproduction number depends on the within-host bacteria load in a complex way, exhibiting multiple peaks. A possible mechanism to account for the switch in shedding patterns of the bacteria in this disease is included in the within-host model, and its effect can be seen in the epidemiological reproduction model.     

The within host dynamics of Mycobacterium avium ssp. paratuberculosis infection in cattle: where time and place matter

Johne’s disease or paratuberculosis, caused by Mycobacterium avium subsp. paratuberculosis (MAP), occurs in domestic and wild animals worldwide, causing a significant economic loss to livestock industries. After a prolonged incubation time, infected cattle shed MAP bacilli into feces and spread the disease to an uninfected animal population. It is largely unknown how (or whether) the interplay between the pathogen and the host immunity determines timing of shedding after the long incubation time. Such information would provide an understanding of pathogenesis in individual animals and the epidemiology of MAP infection in animal populations. In this review, we summarize current knowledge of bovine Johne’s disease pathology, pathogenesis, immunology and genetics. We discuss knowledge gaps that direly need to be addressed to provide a science-based approach to diagnostics and (immuno)prophylaxis. These knowledge gaps are related to anatomical/clinical manifestation of MAP invasion, interaction of bacteria with phagocytes, granuloma formation, shedding, establishment and kinetics of adaptive immune responses in the pathogenesis of the disease. These topics are discussed at the molecular, cellular and tissue levels with special attention to the within host dynamics including the temporal and the spatial context relevant for the various host-pathogen interactions.