Polyetheretherketone--cytotoxicity and mutagenicity in vitro

The results of the incubation of polyetheretherketone (PEEK) fibre material with seven different genotype variants of salmonella bacterium showed with and without an external metabolic activation system (S9) with no mutagenic or cytotoxic activity of the test material. In the so-called "plate incorporation test" in which the PEEK raw material is finely cut and applied direct to the agar plate without the addition of solvent there was, as expected, no evidence of cytotoxic or mutagenic effects. In the HPRT test there was a significant increase in the number of mutants per dish, both after addition of N-acetylaminofluorene and N-methyl-N'-nitro-N-nitrosoguanidine (with and without an external metabolic activation system = +S9), but not after treatment of the cells with PEEK-DMSO-eluate. This means that the PEEK material under study did not release any substances that cause V79 cells to mutate. The investigation of the toxic reaction on the material under study revealed that the number of surviving colonies per 10(5) surviving cells lay within the range of or below the solvent control even in the presence of high PEEK concentrations (5.0 microg/ml). Therefore, in summary, the study produced no evidence of cell damage caused by PEEK.     

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.     

Carcinogenicity and DNA adduct formation observed in ACI rats after long-term treatment with madder root, Rubia tinctorum L

Madder root, Rubia tinctorum L., is a traditional herbal medicine used against kidney stones. Recently we reported that lucidin, a hydroxyanthraquinone derivative present in this plant, is mutagenic in bacteria and mammalian cells. We also demonstrated the formation of DNA adducts in tissue culture and mice after treatment with this compound. To elucidate the possible carcinogenicity of madder root, three groups of male and female ACI rats received either a normal diet or a diet supplemented with 1 or 10% drug for a total period of 780 days. Weight gain and morbidity were not different among the three groups. Non- neoplastic lesions related to the treatment were evident in the liver and kidneys of both sexes. Moreover, dose-dependent increases in benign and malignant tumour formation were observed in the liver and kidneys of treated animals. 32P-post-labelling analysis showed an increase in the overall level of DNA adducts observed in the liver, kidney and colon of rats treated with 10% madder root in the diet for 2 weeks. HPLC analysis of 32P-labelled DNA adducts revealed a peak co-migrating with an adduct obtained after in vitro treatment of deoxyguanosine-3'- phosphate with lucidin. These observations suggest that the use of madder root for medicinal purposes is associated with a carcinogenic risk.      

Topical Administration of Tranexamic Acid in Primary Total Hip and Total Knee Arthroplasty

Major blood loss is a known potential complication in total hip and total knee arthroplasty. We conducted a prospective, stratified, randomized, double-blind, placebo-controlled trial that evaluated 100 patients undergoing total knee or total hip arthroplasty to evaluate the effect on blood loss using the topical application of tranexamic acid. Participants received either 2 g of topical tranexamic acid or the equivalent volume of placebo into the joint prior to surgical closure. Tranexamic acid resulted in a lower mean maximum decline in postoperative hemoglobin levels when compared to placebo (P = 0.013). Patients in the tranexamic acid group demonstrated an improved but non-significant reduction in the units of blood transfused compared to placebo (P = 0.423). There was no clinically significant increase in complications in the tranexamic acid group, including no incidence of venous thromboembolism.     

A putative oncogenic role for MPP11 in head and neck squamous cell cancer

Genetic alterations of chromosome 7 are common in human cancer. Furthermore, previous studies have supported the presence of a gene important in a broad range of cancers at 7q22-31.1. There is evidence that supports an oncogenic function for this putative gene, as well as evidence that supports a tumor suppressive role. In this study, we used a cross-species candidate gene approach in combination with physical mapping to identify MPP11 as a candidate for the putative cancer-related activity at 7q22-31.1. We then analyzed primary head and neck squamous cell tumors (HNSCCs) for loss of heterozygosity/allelic imbalance (LOH/AI) at the MPP11 genomic locus. Thirty-eight percent of tumors examined displayed LOH/AI involving the MPP11 genomic locus. Mutation analysis of MPP11 in the latter samples did not identify any inactivating mutations. However, immunohistochemical staining of primary tumor sections and Western blot analysis of HNSCC cell lines revealed a tumor-specific high level of expression of MPP11p. Fluorescence in situ hybridization analysis done on the cell lines identified increased chromosome 7 copy number with a concomitant increase in MPP11 copy number. These results suggest an oncogenic role for MPP11 in HNSCC.     

Induction of erythroid differentiation by the anthracycline antitumor antibiotics, aclacinomycin A, musettamycin and marcellomycin

The oligosaccharide anthracycline aclacinomycin A is of considerable clinical interest since, in comparison to adriamycin and daunomycin, the compound exhibits reduced cardiac toxicity and is devoid of mutagenicity/carcinogenicity. In addition, induction of differentiation in the human promyelocytic leukemia cell line HL 60 and possibly in one case of human acute myeloblastic leukemia by aclacinomycin A has been observed. Our data indicate that aclacinomycin A and related compounds, such as musettamycin and marcellomycin, are extremely potent inducers of differentiation in mouse (Friend leukemia cells, clone F4-6), rat (rat erythroleukemia, clone D5A1), and human erythroid cell lines (K 562 cell line) and that the relative inductive potency of marcellomycin and musettamycin, in general, is higher than that of aclacinomycin A. This potency difference may be due to the presence of a Cl-hydroxyl group in the aglycone of the marcellomycin and musettamycin molecule. Thus, oligosaccharide anthracyclines are a new class of inducers of erythroid differentiation. The high potency of these compounds, the possibility to study structure-activity relationships relative to their inductive potency and the fact that they induce erythroid differentiation in cells of different species as well as granulocytic differentiation in human cells should facilitate the study of basic mechanisms of hemopoietic differentiation. In addition, the therapeutical significance of these anthracycline effects should be investigated by studying, comparatively, the differentiation-inducing and antitumor effects of these compounds in primary leukemic cell cultures from patients.