The response of Escherichia coli to the alkylating agents chloroacetaldehyde and styrene oxide.

DNA damage is ubiquitous and can arise from endogenous or exogenous sources. DNA-damaging alkylating agents are present in environmental toxicants as well as in cancer chemotherapy drugs and are a constant threat, which can lead to mutations or cell death. All organisms have multiple DNA repair and DNA damage tolerance pathways to resist the potentially negative effects of exposure to alkylating agents. In bacteria, many of the genes in these pathways are regulated as part of the SOS reponse or the adaptive response. In this work, we probed the cellular responses to the alkylating agents chloroacetaldehyde (CAA), which is a metabolite of 1,2-dichloroethane used to produce polyvinyl chloride, and styrene oxide (SO), a major metabolite of styrene used in the production of polystyrene and other polymers. Vinyl chloride and styrene are produced on an industrial scale of billions of kilograms annually and thus have a high potential for environmental exposure. To identify stress response genes in E. coli that are responsible for tolerance to the reactive metabolites CAA and SO, we used libraries of transcriptional reporters and gene deletion strains. In response to both alkylating agents, genes associated with several different stress pathways were upregulated, including protein, membrane, and oxidative stress, as well as DNA damage. E. coli strains lacking genes involved in base excision repair and nucleotide excision repair were sensitive to SO, whereas strains lacking recA and the SOS gene ybfE were sensitive to both alkylating agents tested. This work indicates the varied systems involved in cellular responses to alkylating agents, and highlights the specific DNA repair genes involved in the responses.

Platelet decoys inhibit thrombosis and prevent metastatic tumor formation in preclinical models.

Platelets are crucial for normal hemostasis; however, their hyperactivation also contributes to many potentially lethal pathologies including myocardial infarction, stroke, and cancer. We hypothesized that modified platelets lacking their aggregation and activation capacity could act as reversible inhibitors of platelet activation cascades. Here, we describe the development of detergent-extracted human modified platelets (platelet decoys) that retained platelet binding functions but were incapable of functional activation and aggregation. Platelet decoys inhibited aggregation and adhesion of platelets on thrombogenic surfaces in vitro, which could be immediately reversed by the addition of normal platelets; in vivo in a rabbit model, pretreatment with platelet decoys inhibited arterial injury-induced thromboembolism. Decoys also interfered with platelet-mediated human breast cancer cell aggregation, and their presence decreased cancer cell arrest and extravasation in a microfluidic human microvasculature on a chip. In a mouse model of metastasis, simultaneous injection of the platelet decoys with tumor cells inhibited metastatic tumor growth. Thus, our results suggest that platelet decoys might represent an effective strategy for obtaining antithrombotic and antimetastatic effects.

Infectious Disease in Contact Sports.

CONTEXT:: Infections are common in contact sports. This review aims to describe the epidemiology, presenting signs and symptoms, treatment guidelines, and regulations for several common infections seen in contact sport athletes. The conditions discussed include bacterial skin infections, herpes simplex virus, molluscum contagiosum, common warts, tinea, scabies, head lice, conjunctivitis, human immunodeficiency virus, hepatitis C virus, and vaccine-preventable illnesses. EVIDENCE ACQUISITION:: Searches were performed across PubMed and MEDLINE research databases. In addition, general internet search engine results and reviews of reference lists of relevant papers were used to identify additional sources of evidence. STUDY DESIGN:: Clinical review. LEVEL OF EVIDENCE:: Level 4. RESULTS:: The most common infections seen in contact sport athletes include bacterial skin infections, herpes simplex virus, molluscum contagiosum, common warts, tinea, scabies, head lice, conjunctivitis, and vaccine-preventable illnesses. Other infections, including human immunodeficiency virus and hepatitis C, are uncommon but potentially life threatening. CONCLUSION:: Infections are common in contact sport athletes. The provider who cares for these athletes should be aware of the most common infections and their appropriate management. Early diagnosis and appropriate clinical management are important for treating the infected athlete, minimizing risk of transmission, minimizing time lost from competition, and preventing large outbreaks.

Stump Appendicitis.

Abdominal pain is a frequent problem encountered in the emergency department, and acute appendicitis is a well-recognized diagnosis. Laparoscopic appendectomy has become one of the most common surgical procedures in the United States. Patients with a history of appendectomy may experience recurrent right lower quadrant abdominal pain from an infrequently encountered complication that may occur when the residual appendix becomes obstructed and inflamed. We describe two cases of stump appendicitis in pediatric patients with a review of clinical and imaging findings and surgical management.

Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression.

Cigarette smoking is implicated in numerous diseases, including emphysema and lung cancer. The clinical expression of lung disease in smokers is not well explained by currently defined variations in gene expression or simple differences in smoking exposure. Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking-related lung disease. Significant gene expression changes in alveolar macrophages from smokers have been identified. However, the mechanism for these changes remains unknown. One potential mechanism for smoking-altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene-coding sequences. In this study, alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined. We found differential methylation in genes from immune-system and inflammatory pathways. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune-system and inflammatory pathways. A significant number of genes with smoking-altered mRNA expression had inverse changes in methylation status. One gene highlighted by this data was the FLT1, and further studies found particular up-regulation of a splice variant encoding a soluble inhibitory form of the receptor. In conclusion, chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages.