The Cytochrome P450 Inhibitor, Ketoconazole, Inhibits Oxidized Linoleic Acid Metabolite-Mediated Peripheral Inflammatory Pain

BACKGROUND: Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous agonists to the transient receptor potential V1 (TRPV1) receptor. Although TRPV1 mediates inflammatory heat hyperalgesia, it is not known if the OLAMs contribute to the peripheral activation of this receptor during tissue inflammation. In the present study, we evaluated whether the OLAM system is activated during inflammation and whether cytochrome P450 enzymes mediate OLAM contributions to heat hyperalgesia using the complete Freund’s adjuvant (CFA) model of inflammation. RESULTS: Our results demonstrate that the intraplantar (ipl) injection of anti-OLAM antibodies significantly reversed CFA-induced heat hyperalgesia. Moreover, application of lipid extracts from inflamed rat skin to cultured sensory neurons triggered a significant release of iCGRP that is blocked by co-treatment with I-RTX, a TRPV1 antagonist. To determine the role of CYP enzymes in mediating OLAM effects, we used a broad spectrum CYP inhibitor, ketoconazole. Pretreatment with ketoconazole inhibited the release of TRPV1 agonists in lipid extracts from inflamed skin and significantly reversed CFA-induced heat hyperalgesia by a peripheral mechanism of action. Moreover, the ipl injection of linoleic acid to rats 24 hr after CFA evoked spontaneous nocifensive behaviors that were significantly reduced by capsazepine, by knockout of the TRPV1 gene, or by pretreatment with either anti-OLAM antibodies or ketoconazole. CONCLUSIONS: Taken together, our data suggests that OLAMs contribute to inflammatory nociception in the periphery and that cytochrome P450 enzymes play a crucial role in mediating OLAM contributions to inflammatory heat hyperalgesia

Pulmonary nodules and CT screening: the past, present and future

Lung cancer screening has come a long way since the early studies with chest X-ray. Advancing technology and progress in the processing of images have enabled low dose CT to be tried and tested, and evidence suggests its use can result in a significant mortality benefit. There are several issues that need refining in order to successfully implement screening in the UK and elsewhere. Some countries have started patchy implementation of screening and there is increased recognition that the appropriate management of pulmonary nodules is crucial to optimise benefits of early detection, while reducing harm caused by inappropriate medical intervention. This review summarises and differentiates the many recent guidelines on pulmonary nodule management, discusses screening activity in other countries and exposes the present barriers to implementation in the UK

Mapping the spectrum of psychological and behavioural responses to low-dose CT lung cancer screening offered within a Lung Health Check

BACKGROUND: Research on the psychological impact of low-dose computed tomography (LDCT) lung cancer screening has typically been narrow in scope and restricted to the trial setting. OBJECTIVE: To explore the range of psychological and behavioural responses to LDCT screening offered as part of a Lung Heath Check (LHC), including lung cancer risk assessment, spirometry testing, a carbon monoxide reading and smoking cessation advice. METHODS: Semi-structured interviews were carried out with 28 current and former smokers (aged 60-75), who had undergone LDCT screening as part of a LHC appointment and mostly received an incidental or indeterminate result (n = 23). Framework analysis was used to map the spectrum of responses participants had across the LHC appointment and screening pathway, to their LDCT results and to surveillance. RESULTS: Interviewees reported a diverse range of both positive and negative psychological responses, beginning at invitation and spanning the entire LHC appointment (including spirometry) and LDCT screening pathway. Similarly, positive behavioural responses extended beyond smoking cessation to include anticipated implications for other cancer prevention and early detection behaviours, such as symptom presentation. Individual differences in responses appeared to be influenced by smoking status and LDCT result, as well as modifiable factors including perceived risk and health status, social support, competing priorities, fatalism and perceived stigma. CONCLUSIONS: The diverse ways in which participants responded to screening, both psychologically and behaviourally, should direct a broader research agenda to ensure all stages of screening delivery and communication are designed to promote well-being, motivate positive behaviour change and maximize patient benefit

Preferences for Decision Control among a High-Risk Cohort Offered Lung Cancer Screening: A Brief Report of Secondary Analyses from the Lung Screen Uptake Trial (LSUT)

Background. Personal autonomy in lung cancer screening is advocated internationally, but health systems diverge in their approach, mandating either shared decision making (with a health care professional) or individual decision making. Studies of other cancer screening programs have found that individual preferences for the level of involvement in screening decisions vary across different sociodemographic groups and that aligning approaches with individual preferences has the potential to improve uptake. Method. For the first time, we examined preferences for decision control among a cohort of UK-based high-risk lung cancer screening candidates (N = 727). We used descriptive statistics to report the distribution of preferences and chi-square tests to examine associations between decision preferences and sociodemographic variables. Results. Most (69.7%) preferred to be involved in the decision with varying degrees of input from a health care professional. Few (10.2%) wanted to make the decision alone. Preferences were also associated with educational attainment. Conclusion. These findings suggest one-size-fits-all approaches may be inadequate in meeting diverse preferences, particularly those placing sole onus on the individual. HIGHLIGHTS: Preferences for involvement in decision making about lung cancer screening are heterogeneous among high-risk individuals in the United Kingdom and vary by educational attainment.Further work is needed to understand how policy makers might implement hybrid approaches to accommodate individual preferences and optimize lung cancer screening program outcomes