Anal human papilloma viral infection and squamous cell carcinoma: Need objective biomarkers for risk assessment and surveillance guidelines

High grade anal intraepithelial neoplasia due to human papilloma viral (HPV) infections is a precursor lesion for squamous cell carcinoma especially in high risk populations. Frequent examination and anal biopsies remain unpopular with patients; moreover they are also risk factors for chronic pain, scarring and sphincter injury. There is lack of uniform, surveillance methods and guidelines for anal HPV specifically the intervals between exam and biopsies. The aim of this editorial is to discuss the intervals for surveillance exam and biopsy, based on specific HPV related biomarkers? Currently there are no published randomized controlled trials documenting the effectiveness of anal screening and surveillance programs to reduce the incidence, morbidity and mortality of anal cancers. In contrast, the currently approved screening and surveillance methods available for HPV related cervical cancer includes cytology, HPV DNA test, P16 or combined P16/Ki-67 index and HPV E/6 and E/7 mRNA test. There are very few studies performed to determine the efficacy of these tests in HPV related anal pre-cancerous lesions. The relevance of these biomarkers is discussed in this editorial. Longitudinal prospective research is needed to confirm the effectiveness of these molecular biomarkers that include high risk HPV serotyping, P16 immuno-histiochemistry and E6/E7 mRNA profiling on biopsies to elucidate and establish surveillance guidelines.     

Fulminant Cytomegalovirus Myocarditis in an Immunocompetent Host: Resolution with Oral Valganciclovir

We report a case of fulminant myocarditis after a primary cytomegalovirus infection, in a previously healthy 72-year-old woman. The infection underwent clinical and immunologic resolution consequent to treatment with oral valganciclovir. In an immunocompetent host, the primary cytomegalovirus infection is usually asymptomatic or manifests itself as a heterophile-negative mononucleosis-like syndrome. Cytomegalovirus myocarditis is uncommon in immunocompetent patients. After presenting our case, we review the literature on cytomegalovirus myocarditis in immunocompetent individuals.     

Prostaglandin E2 Promotes UV Radiation-Induced Immune Suppression through DNA Hypermethylation

Exposure of mice to UV radiation results in suppression of the contact hypersensitivity (CHS) response. Here, we report that the UV-induced suppression of CHS is associated with increases in the levels of cyclooxygenase-2 (COX-2), prostaglandin E₂ (PGE₂), and PGE₂ receptors in the exposed skin. UV radiation-induced suppression of CHS was inhibited by topical treatment of the skin with celecoxib or indomethacin (inhibitors of COX-2) or AH6809 (an EP2 antagonist). Moreover, mice deficient in COX-2 were found to be resistant to UV-induced suppression of CHS. The exposure of wild-typemice to UVB radiation resulted in DNA hypermethylation, increased DNA methyltransferase (Dnmt) activity, and elevated levels of Dnmt1, Dnmt3a, and Dnmt3b proteins in the skin, and these responses were downregulated on topical treatment of the site of exposure after irradiation with indomethacin or EP2 antagonist. Topical treatment of UVB-exposed COX-2-deficient mice with PGE₂ enhanced the UVB-induced suppression of CHS as well as global DNA methylation and elevated the levels of Dnmt activity and Dnmt proteins in the skin. Intraperitoneal injection of 5-aza-2′-deoxycytidine (5-Aza-dc), a DNA demethylating agent, restored the CHS response to 2,4-dinitrofluorobenzene in UVB-exposed skin and this was associated with the reduction in global DNA methylation and Dnmt activity and reduced levels of Dnmt proteins. Furthermore, treatment with 5-Aza-dc reversed the effect of PGE₂ on UV-induced suppression of CHS in COX-2-deficient mice. These findings reveal a previously unrecognized role for PGE₂ in the promotion of UVB-induced immunosuppression and indicate that it is mediated through PGE₂ regulation of DNA methylation.     

Imaging of Vulnerable Plaques Using Near-Infrared Spectroscopy for Risk Stratification of Atherosclerosis

Large randomized trials have shown that lowering the concentration of LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, with further benefit emerging during each year of treatment allocation. But, limited evidence is available about the long-term efficacy and safety of statin treatment. Long-term follow-up of surviving trial participants allows direct assessment of the benefits (and any hazards) of a sustained reduction in LDL cholesterol concentration during the post-trial period. Post-trial follow-up of several large statin trials (of which the Heart Protection Study was the largest) confirms that the substantial absolute benefits and cost-effectiveness of statin therapy were, in fact, underestimated in previous analyses restricted to the “in-trial” periods of randomized studies. Reassuringly, no adverse effects on cancer incidence or non-vascular mortality emerged during the extended follow-up of the Heart Protection Study. These findings support the prompt initiation and long-term continuation of statin therapy in individuals at increased vascular risk.     

Effect of cardiopulmonary bypass on cytochrome P450 enzyme activity: implications for pharmacotherapy

For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities of cytochrome P450 (CYP) isoenzymes. PK changes during cardiac surgery with CPB have the potential to adversely affect the safety and efficacy of pharmacotherapy and increase the risk of drug–drug interactions. Clinically significant changes in drug PK during CPB are likely to be prominent for drugs where CYP metabolism is a major clearance (CL) mechanism. However, clinical data from patients undergoing CPB surgery in support of this hypothesis are lacking, leaving a significant knowledge gap. In this review, we address the effects of CPB on the release of pro-inflammatory cytokines, in surgeries with and without CPB, both pre and post initiation of surgery. We reviewed literature to explore the relationship between the release of pro-inflammatory cytokines, and the expression and activities of CYP enzymes. Through this approach, we provide new insight on the effects of CPB on the PK of drugs administered to patients in the clinical setting. Future research to address this knowledge gap will have considerable impact to assist clinicians with optimizing pharmacotherapy in this patient population.