Pain and its interference with daily living in relation to cancer: a comparative population-based study of 16,053 cancer survivors and 106,345 people without cancer.

BACKGROUND: Pain is a common, debilitating, and feared symptom, including among cancer survivors. However, large-scale population-based evidence on pain and its impact in cancer survivors is limited. We quantified the prevalence of pain in community-dwelling people with and without cancer, and its relation to physical functioning, psychological distress, and quality of life (QoL). METHODS: Questionnaire data from participants in the 45 and Up Study (Wave 2, n = 122,398, 2012-2015, mean age = 60.8 years), an Australian population-based cohort study, were linked to cancer registration data to ascertain prior cancer diagnoses. Modified Poisson regression estimated age- and sex-adjusted prevalence ratios (PRs) for bodily pain and pain sufficient to interfere with daily activities (high-impact pain) in people with versus without cancer, for 13 cancer types, overall and according to clinical, personal, and health characteristics. The relation of high-impact pain to physical and mental health outcomes was quantified in people with and without cancer. RESULTS: Overall, 34.9% (5,436/15,570) of cancer survivors and 31.3% (32,471/103,604) of participants without cancer reported bodily pain (PR = 1.07 [95% CI = 1.05-1.10]), and 15.9% (2,468/15,550) versus 13.1% (13,573/103,623), respectively, reported high-impact pain (PR = 1.13 [1.09-1.18]). Pain was greater with more recent cancer diagnosis, more advanced disease, and recent cancer treatment. High-impact pain varied by cancer type; compared to cancer-free participants, PRs were: 2.23 (1.71-2.90) for multiple myeloma; 1.87 (1.53-2.29) for lung cancer; 1.06 (0.98-1.16) for breast cancer; 1.05 (0.94-1.17) for colorectal cancer; 1.04 (0.96-1.13) for prostate cancer; and 1.02 (0.92-1.12) for melanoma. Regardless of cancer diagnosis, high-impact pain was strongly related to impaired physical functioning, psychological distress, and reduced QoL. CONCLUSIONS: Pain is common, interfering with daily life in around one-in-eight older community-dwelling participants. Pain was elevated overall in cancer survivors, particularly for certain cancer types, around diagnosis and treatment, and with advanced disease. However, pain was comparable to population levels for many common cancers, including breast, prostate and colorectal cancer, and melanoma.

GenomicDistributions: fast analysis of genomic intervals with Bioconductor.

BACKGROUND: Epigenome analysis relies on defined sets of genomic regions output by widely used assays such as ChIP-seq and ATAC-seq. Statistical analysis and visualization of genomic region sets is essential to answer biological questions in gene regulation. As the epigenomics community continues generating data, there will be an increasing need for software tools that can efficiently deal with more abundant and larger genomic region sets. Here, we introduce GenomicDistributions, an R package for fast and easy summarization and visualization of genomic region data. RESULTS: GenomicDistributions offers a broad selection of functions to calculate properties of genomic region sets, such as feature distances, genomic partition overlaps, and more. GenomicDistributions functions are meticulously optimized for best-in-class speed and generally outperform comparable functions in existing R packages. GenomicDistributions also offers plotting functions that produce editable ggplot objects. All GenomicDistributions functions follow a uniform naming scheme and can handle either single or multiple region set inputs. CONCLUSIONS: GenomicDistributions offers a fast and scalable tool for exploratory genomic region set analysis and visualization. GenomicDistributions excels in user-friendliness, flexibility of outputs, breadth of functions, and computational performance. GenomicDistributions is available from Bioconductor ( https://bioconductor.org/packages/release/bioc/html/GenomicDistributions.html ).

Monte Carlo molecular simulation of solution and surface-bound DNA hybridization of short oligomers at varying surface densities.

DNA microarrays utilize surface bound sequences to probe for target sequences in samples of interest, and density of surface coverage plays an important role in any duplex formation and subsequent detection. Here, Monte Carlo molecular simulations utilize a modified coarse-grained DNA model to calculate the impact of binding density and arrangement as well as temperature on duplex structure and hydrogen bonding patterns for two different undecamer sequences. Results indicate a modest, sequence-dependent increase in dissociation related to the proximity of neighboring duplexes but little impact on duplex structure or hydrogen bonding pattern.

Workforce participation in relation to cancer diagnosis, type and stage: Australian population-based study of 163,556 middle-aged people.

PURPOSE: To quantify the relationship of cancer diagnosis to workforce participation in Australia, according to cancer type, clinical features and personal characteristics. METHODS: Questionnaire data (2006-2009) from participants aged 45-64 years (n=163,556) from the population-based 45 and Up Study (n=267,153) in New South Wales, Australia, were linked to cancer registrations to ascertain cancer diagnoses up to enrolment. Modified Poisson regression estimated age- and sex-adjusted prevalence ratios (PRs) for non-participation in the paid workforce-in participants with cancer (n=8,333) versus without (n=155,223), for 13 cancer types. RESULTS: Overall, 42% of cancer survivors and 29% of people without cancer were out of the workforce (PR=1.18; 95%CI=1.15-1.21). Workforce non-participation varied substantively by cancer type, being greatest for multiple myeloma (1.83; 1.53-2.18), oesophageal (1.70; 1.13-2.58) and lung cancer (1.68; 1.45-1.93) and moderate for colorectal (1.23; 1.15-1.33), breast (1.11; 1.06-1.16) and prostate cancer (1.06; 0.99-1.13). Long-term survivors, 5 or more years post-diagnosis, had 12% (7-16%) greater non-participation than people without cancer, and non-participation was greater with recent diagnosis, treatment or advanced stage. Physical disability contributed substantively to reduced workforce participation, regardless of cancer diagnosis. CONCLUSIONS: Cancer survivors aged 45-64 continue to participate in the workforce. However, participation is lower than in people without cancer, varying by cancer type, and is reduced particularly around the time of diagnosis and treatment and with advanced disease. IMPLICATIONS FOR CANCER SURVIVORS: While many cancer survivors continue with paid work, participation is reduced. Workforce retention support should be tailored to survivor preferences, cancer type and cancer journey stage.

Disability, psychological distress and quality of life in relation to cancer diagnosis and cancer type: population-based Australian study of 22,505 cancer survivors and 244,000 people without cancer.

BACKGROUND: Improved survival means that cancer is increasingly becoming a chronic disease. Understanding and improving functional outcomes are critical to optimising survivorship. We quantified physical and mental health-related outcomes in people with versus without cancer, according to cancer type. METHODS: Questionnaire data from an Australian population-based cohort study (45 and Up Study (n = 267,153)) were linked to cancer registration data to ascertain cancer diagnoses up to enrolment. Modified Poisson regression estimated age- and sex-adjusted prevalence ratios (PRs) for adverse person-centred outcomes-severe physical functional limitations (disability), moderate/high psychological distress and fair/poor quality of life (QoL)-in participants with versus without cancer, for 13 cancer types. RESULTS: Compared to participants without cancer (n = 244,000), cancer survivors (n = 22,505) had greater disability (20.6% versus 12.6%, respectively, PR = 1.28, 95%CI = (1.25-1.32)), psychological (22.2% versus 23.5%, 1.05 (1.02-1.08)) and poor/fair QoL (15.2% versus 10.2%; 1.28 (1.24-1.32)). The outcomes varied by cancer type, being worse for multiple myeloma (PRs versus participants without cancer for disability 3.10, 2.56-3.77; distress 1.53, 1.20-1.96; poor/fair QoL 2.40, 1.87-3.07), lung cancer (disability 2.81, 2.50-3.15; distress 1.67, 1.46-1.92; poor/fair QoL 2.53, 2.21-2.91) and non-Hodgkin's lymphoma (disability 1.56, 1.37-1.78; distress 1.20, 1.05-1.36; poor/fair QoL 1.66, 1.44-1.92) and closer to those in people without cancer for breast cancer (disability 1.23, 1.16-1.32; distress 0.95, 0.90-1.01; poor/fair QoL 1.15, 1.05-1.25), prostate cancer (disability 1.11, 1.04-1.19; distress 1.09, 1.02-1.15; poor/fair QoL 1.15, 1.08-1.23) and melanoma (disability 1.02, 0.94-1.10; distress 0.96, 0.89-1.03; poor/fair QoL 0.92, 0.83-1.01). Outcomes were worse with recent diagnosis and treatment and advanced stage. Physical disability in cancer survivors was greater in all population subgroups examined and was a major contributor to adverse distress and QoL outcomes. CONCLUSIONS: Physical disability, distress and reduced QoL are common after cancer and vary according to cancer type suggesting priority areas for research, and care and support.

How have advances in CT dosimetry software impacted estimates of CT radiation dose and cancer incidence? A comparison of CT dosimetry software: Implications for past and future research.

OBJECTIVE: Organ radiation dose from a CT scan, calculated by CT dosimetry software, can be combined with cancer risk data to estimate cancer incidence resulting from CT exposure. We aim to determine to what extent the use of improved anatomical representation of the adult human body "phantom" in CT dosimetry software impacts estimates of radiation dose and cancer incidence, to inform comparison of past and future research. METHODS: We collected 20 adult cases for each of three CT protocols (abdomen/pelvis, chest and head) from each of five public hospitals (random sample) (January-April inclusive 2010) and three private clinics (self-report). Organ equivalent and effective dose were calculated using both ImPACT (mathematical phantom) and NCICT (voxelised phantom) software. Bland-Altman plots demonstrate agreement and Passing-Bablok regression reports systematic, proportional or random differences between results. We modelled the estimated lifetime attributable risk of cancer from a single exposure for each protocol, using age-sex specific risk-coefficients from the Biologic Effects of Ionizing Radiation VII report. RESULTS: For the majority of organs used in epidemiological studies of cancer incidence, the NCICT software (voxelised) provided higher dose estimates. Across the lifespan NCICT resulted in cancer estimates 2.9%-6.6% and 14.8%-16.3% higher in males and females (abdomen/pelvis) and 7.6%-19.7% and 12.9%-26.5% higher in males and females respectively (chest protocol). For the head protocol overall cancer estimates were lower for NCICT, but with greatest disparity, >30% at times. CONCLUSION: When the results of previous studies estimating CT dose and cancer incidence are compared to more recent, or future, studies the dosimetry software must be considered. Any change in radiation dose or cancer risk may be attributable to the software and phantom used, rather than-or in addition to-changes in scanning practice. Studies using dosimetry software to estimate radiation dose should describe software comprehensively to facilitate comparison with past and future research.

Development of a cancer pain self-management resource to address patient, provider, and health system barriers to care.

OBJECTIVE: The majority of self-management interventions are designed with a narrow focus on patient skills and fail to consider their potential as "catalysts" for improving care delivery. A project was undertaken to develop a patient self-management resource to support evidence-based, person-centered care for cancer pain and overcome barriers at the levels of the patient, provider, and health system. METHOD: The project used a mixed-method design with concurrent triangulation, including the following: a national online survey of current practice; two systematic reviews of cancer pain needs and education; a desktop review of online patient pain diaries and other related resources; consultation with stakeholders; and interviews with patients regarding acceptability and usefulness of a draft resource. RESULT: Findings suggested that an optimal self-management resource should encourage pain reporting, build patients' sense of control, and support communication with providers and coordination between services. Each of these characteristics was identified as important in overcoming established barriers to cancer pain care. A pain self-management resource was developed to include: (1) a template for setting specific, measureable, achievable, relevant and time-bound goals of care, as well as identifying potential obstacles and ways to overcome these; and (2) a pain management plan detailing exacerbating and alleviating factors, current strategies for management, and contacts for support. SIGNIFICANCE OF RESULTS: Self-management resources have the potential for addressing barriers not only at the patient level, but also at provider and health system levels. A cluster randomized controlled trial is under way to test effectiveness of the resource designed in this project in combination with pain screening, audit and feedback, and provider education. More research of this kind is needed to understand how interventions at different levels can be optimally combined to overcome barriers and improve care.

It's about Time: Effects of Physical Exertion on Duration Estimates.

BACKGROUND: Task duration is a fundamental aspect of exercise, but little is known about how completed bouts of physical activity are perceived. Consequently, the purpose of the five experiments conducted for this investigation was to examine the effects of engaging in physical tasks on retrospective duration estimates with college student participants. METHODS: Across the five experiments, participants were 113 college students (82 women, 31 men). In Experiments 1 and 2, participants provided duration estimates of a period spent engaging in physical activity or rest. In Experiments 3, 4, and 5, participants provided duration estimates of periods spent engaged in physical tasks of high intensity and low intensity. RESULTS: In Experiments 1, 2, and 3, participants engaged in physical activity tended to perceive durations as shorter than participants at rest. When completing less familiar tasks (Experiments 4 and 5), however, participants recalled a high intensity bout of physical activity as lasting longer than a low intensity bout of physical activity of comparable duration. Cohen's d values for physical activity effects on duration estimates ranged from 0.40 to 1.60. CONCLUSION: The findings, which partially support a contextual-change interpretation, suggest that factors, such as perceived exertion and task familiarity, affect retrospective duration estimates.

Oxidation of tartrazine with ultraviolet light emitting diodes: pH and duty cycles effects.

The presence of tartrazine (TAR) in the water cycle poses serious threats to human health. This study investigated the used of light emitting diodes (LEDs) in the advanced oxidation of TAR under different pH and duty cycle (DC) conditions. The first order reaction rate constant for TAR oxidation was positively correlated with DC, negatively correlated with pH, and typically greatest at pH 6. Chemical byproduct analysis indicated that OH addition, H abstraction, and electron transfer without molecule transfer were among the relevant reaction mechanisms for TAR degradation. Six byproducts were identified, four were reported for the first time, and two demonstrated that TAR rings were cleaved. This research is the first to determine the optimal pH for UVLED-driven oxidation of TAR and the first to identify new TAR-related byproducts from UVLED-based water treatment.

The prevalence, severity, and correlates of psychological distress and impaired health-related quality of life following treatment for testicular cancer: a survivorship study.

PURPOSE: This study aimed to establish the prevalence, severity, and correlates of psychological distress and impaired generic health-related quality of life (HRQOL) in testicular cancer (TC) survivors. METHODS: Men who had completed active anti-cancer treatment for TC between 6 months and 5 years previously showing no evidence of recurrence were recruited from 14 Australian cancer centers from September 2009 to February 2011. Participants completed a self-report questionnaire measuring demographic, disease, and treatment information, psychological distress (i.e., depression, anxiety, and stress; DASS21), generic health-related quality of life (HRQOL; SF-36v2), TC-specific HRQOL (EORTC QLQ-TC26), coping (MAC), social support (DUFSS), and unmet needs (CaSUN). RESULTS: Of 486 eligible TC survivors, 244 (50.2%) completed the questionnaire. Compared with normative data, TC survivors reported: small but statistically significant increases in mean levels of anxiety and depression; a greater prevalence of moderate to extremely severe anxiety (19%) and depression (20%); and significant deficits to mostly mental aspects of generic HRQOL. The most problematic TC-specific HRQOL issues (e.g., fear of recurrence) were also more mental than physical. In multiple regression analyses, the strongest correlates of psychological distress and impaired generic HRQOL were psychosocial (e.g., helpless/hopeless coping and lower social support) rather than disease or treatment factors. CONCLUSIONS: Generally, TC survivors appear to experience mild psychological distress and HRQOL impairments, while a vulnerable subgroup experience more severe morbidity. IMPLICATIONS FOR CANCER SURVIVORS: There is a need to identify TC survivors at risk of poorer outcomes and for interventions to target the areas of greatest impairment (i.e., psychological distress and mental HRQOL).

Antimicrobial and cell viability measurement of bovine serum albumin capped silver nanoparticles (Ag/BSA) loaded collagen immobilized poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) film.

Bacterial infection of orthopedic devices has been a major concern in joint replacement procedures. Therefore, this study is aimed at formulating collagen immobilized poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) film loaded with bovine serum albumin capped silver nanoparticles (Ag/BSA NPs) to inhibit bacterial growth while retaining/promoting osteoblast cells viability. The nanoparticles loaded collagen immobilized PHBV film was characterized for its composition by X-ray Photoelectron Spectroscopy and Anodic Stripping Voltammetry. The extent of loading of Ag/BSA NPs on collagen immobilized PHBV film was found to depend on the chemistry of the functionalized PHBV film and the concentration of Ag/BSA NPs solution used for loading nanoparticles. Our results showed that more Ag/BSA NPs were loaded on higher molecular weight collagen immobilized PHEMA-g-PHBV film. Maximum loading of Ag/BSA NPs on collagen immobilized PHBV film was observed when 16ppm solution was used for adsorption studies. Colony forming unit and optical density measurements showed broad antimicrobial activity towards Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa at significantly lower concentration i.e., 0.19 and 0.31µg/disc, compared to gentamicin and sulfamethoxazole trimethoprim while MTT assay showed that released nanoparticles from Ag/BSA NPs loaded collagen immobilized PHBV film has no impact on MCTC3-E1 cells viability.

A noise delivery system for multi-animal multi-level whole body ototoxicity studies.

The Naval Medical Research Unit Dayton (NAMRU-D) at Wright-Patterson Air Force Base, Ohio, in conjunction with the U.S. Air Force, studied ototoxic effects of JP-8 in rats. NAMRU-D used a multi-chamber whole body exposure facility for up to 96 test animals and 32 control animals at different exposure levels. The objective was to design a noise delivery system that could provide a white noise source one octave band wide, centered at 8 kHz frequency, delivered from outside the exposure chambers. Sound pressure levels were required to be within ±2 dB at all exposure points within each chamber and within ±2 dB over a 6-h run. Electrodynamic shakers were used to produce input noise in exposure chambers by inducing vibration in chamber plenums. Distribution of sound pressure levels across exposure points was controlled within a ±1.5dB prediction interval (α = 0.05) or better. Stability at a central reference point was controlled over 6-h runs within a ±1 dB prediction interval (α = 0.05) or better. The final system allowed NAMRU-D to deliver noise and whole-body aerosol exposures to multiple animals at different levels simultaneously and study the effects that ototoxins may have on hearing loss.

Adaptation of international guidelines on assessment and management of cancer pain for the Australian context.

AIM: To develop clinical practice guidelines for screening, assessing and managing cancer pain in Australian adults. METHODS: This three-phase project utilized the ADAPTE approach to adapt international cancer pain guidelines for the Australian setting. A Working Party was established to define scope, screen guidelines for adaptation and develop recommendations to support better cancer pain control through screening, assessment, pharmacological and non-pharmacological management, and patient education. Recommendations with limited evidence were referred to Expert Panels for advice before the draft guidelines were opened for public consultation via the Cancer Council Australia Cancer Guidelines Wiki platform in late 2012. All comments were reviewed by the Working Party and the guidelines were revised accordingly. RESULTS: Screening resulted in six international guidelines being included for adaptation - those developed by the Scottish Intercollegiate Guidelines Network (2008), National Health Service Quality Improvement Scotland (2009), National Comprehensive Cancer Network (2012), European Society of Medical Oncology (2011), European Association for Palliative Care (2011, 2012) and National Institute of Clinical Excellence (2012). Guideline adaptation resulted in 55 final recommendations. The guidelines were officially launched in November 2013. CONCLUSION: International guidelines can be efficiently reconfigured for local contexts using the ADAPTE approach. Availability of the guidelines via the Cancer Council Australia Wiki is intended to promote uptake and enable recommendations to be kept up to date. Resources to support implementation will also be made available via the Wiki if found to be effective by a randomized controlled trial commencing in 2015.

Patients' experiences of referral for colorectal cancer.

BACKGROUND: Outcomes for colorectal cancer patients vary significantly. Compared to other countries, Australia has a good record with patient outcomes, yet there is little information available on the referral pathway. This paper explores the views of Australian patients and their experiences of referral for colorectal cancer treatment following diagnosis; the aim was to improve our understanding of the referral pathway and guide the development of future interventions. METHODS: A purposive sampling strategy was used, recruiting 29 patients representing urban and rural areas from 3 Australian states who participated in 4 focus groups. Seven patients provided individual interviews to supplement the data. Recordings were transcribed verbatim, data was coded with NVivo software and analysed thematically before deductive analysis. RESULTS: Four aspects of the referral process were identified by patients, namely detection/diagnosis, referral for initial treatment/specialist care, the roles of the GP/specialist, and the patient's perceived involvement in the process. The referral process was characterised by a lack of patient involvement, with few examples of shared decision-making and few examples of limited choice. However, patients did not always feel they had the knowledge to make informed decisions. Information exchange was highly valued by patients when it occurred, and it increased their satisfaction with the process. Other factors mediating care included the use of the public versus private health system, the quality of information exchange (GP to specialist and GP to patient), continuity of care between GP and specialist, and the extent of information provision when patients moved between specialist and GP care. CONCLUSIONS: Patients described poor GP continuity, ad hoc organisational systems and limited information exchange, at both interpersonal and inter-organisational levels, all leading to sub-optimal care. Implementation of a system of information feedback to GPs and engagement with them might improve information exchange for patients, enabling them to be more involved in improved referral outcomes.

The prevalence and correlates of supportive care needs in testicular cancer survivors: a cross-sectional study.

OBJECTIVE: This cross-sectional study aimed to identify the prevalence and correlates of supportive care needs in testicular cancer (TC) survivors. METHODS: Men who had completed active anti-cancer treatment for TC between 6 months and 5 years previously showing no evidence of recurrence were recruited from 14 Australian cancer centers (September 2009-February 2011). Participants completed a self-report questionnaire measuring sociodemographics, disease, and treatment information, supportive care needs (CaSUN), psychological distress (DASS21) and health-related quality of life (HRQoL; SF36v2). RESULTS: Of the 486 eligible TC survivors invited to participate, 244 completed the questionnaire. Sixty-six percent reported one or more unmet supportive care needs. The mean number of unmet needs was 4.73 (SD = 7.0, Range = 0-34). The most common unmet needs related primarily to existential survivorship issues (e.g., life stress) and relationships (e.g., sex life). Younger age and presence of chronic illness other than TC were significantly associated with higher number of unmet needs. The number of unmet needs was more highly correlated with psychological distress and HRQoL than unmet need strength. CONCLUSIONS: The majority of TC survivors reported one or more unmet needs. Unmet needs regarding existential survivorship issues were frequently reported by TC survivors despite their favorable prognosis. Relationships unmet needs were less prevalent but still more common than in breast and gynecological cancer survivors. These findings appear to be related to the young age of TC survivors. As a higher number of unmet needs is significantly associated with psychological morbidity and impaired HRQoL, interventions addressing this constellation of issues are needed.

Assessment and management of adult cancer pain: a systematic review and synthesis of recent qualitative studies aimed at developing insights for managing barriers and optimizing facilitators within a comprehensive framework of patient care.

CONTEXT: Cancer pain is a common, burdensome problem, which is not well managed despite evidence-based guidelines. OBJECTIVES: To develop insights for managing barriers and optimizing facilitators to adult cancer pain assessment and management within a comprehensive framework of patient care. METHODS: We undertook a systematic review and synthesis of qualitative studies. Medline, PsycINFO, Embase, AMED, CINAHL, and Sociological Abstracts were searched from May 20 to 26, 2011. To be included, the articles had to be published in a peer-reviewed journal since 2000; written in English; and report original qualitative studies on the perspectives of patients, their significant others, or health care providers. Article quality was rated using the checklist of Kitto et al. Thematic synthesis followed a three-stage approach using Evidence for Policy and Practice Information and Co-ordinating Centre-Reviewer 4 software: 1) free line-by-line coding of "Results," 2) organization into "descriptive" themes, and 3) development of "analytical" themes informative to our objective. At Stage 3, a conceptual framework was selected from the peer-reviewed literature according to prima facie "fit" for descriptive themes. RESULTS: Of 659 articles screened, 70 met the criteria, reporting 65 studies with 48 patient, 19 caregiver, and 21 health care provider samples. Authors rarely reported reflexivity or negative cases. Mead and Bower's model of patient-centered care accommodated 85% of the descriptive themes; 12% more related to the caregiver and service/system factors. Three themes could not be accommodated. CONCLUSION: Findings highlight the need to integrate patient/family education within improved communication, individualize care, use more nonpharmacological strategies, empower patients/families to self-manage pain, and reorganize multidisciplinary roles around patient-centered care and outcomes. These conclusions require validation via consensus and intervention trials.

In vivo characterization of inflammatory biomarkers in swine and the impact of flunixin meglumine administration.

Non-steroidal anti-inflammatory drugs (NSAID) are a family of chemicals that function to reduce pain, fever, and inflammation, and they are commonly used in people and animals for this purpose. Currently there are no NSAIDs approved for the management of inflammation in swine due to a lack of validated animal models and suitable biomarkers to assess efficacy. A previous in vitro study examining biomarkers of inflammation identified fourteen genes that were significantly altered in response to Escherichia coli lipopolysaccharide (LPS)-induced inflammation. In the present study, five of those fourteen genes were tested in vivo to determine if the same effects observed in vitro were also observed in vivo. Plasma levels of prostaglandin E(2) (PGE(2)), an essential mediator of fever and inflammation, were also determined. Two groups of swine were stimulated with LPS with the second group also treated with flunixin meglumine. Blood was collected at 0, 1, 3, 6, 8, 24, and 48 h post LPS-stimulation. The RNA was extracted from the blood and quantitative real-time-PCR (qRT-PCR) was utilized to determine the expression patterns of CD1, CD4, serum amyloid A2 (SAA2), Caspase 1, and monocyte chemoattractant protein 1 (MCP-1). The LPS-stimulated animals demonstrated a statistically significant alteration in expression of SAA2 and CD1 at 3h post-stimulation. Flunixin meglumine treated animals' demonstrated reduced expression of CD1 in comparison to the LPS-stimulated swine at 24 and 48 h post LPS-stimulation. Flunixin meglumine treated animals exhibited reduced expression of SAA2 at 48 h post-stimulation compared to LPS-stimulated swine. Swine treated with LPS demonstrated statistically significant increases in plasma PGE(2) at 1h post-stimulation. Swine treated with flunixin meglumine had no increase in plasma PGE(2) levels at any time. These results demonstrate that PGE(2) production, along with two out of five genes (SAA2 and CD1) have the potential to serve as early biomarkers of inflammation as well as indicators of NSAID efficacy.

Conformational analysis of 6α- and 6ß-naltrexol and derivatives and relationship to opioid receptor affinity.

Naltrexol and its C6 α and ß desoxy, iodo, mesyl, tosyl, trifyl, dimethylcarbamyl, and diphenylcarbamyl derivatives were studied in their energy-minimized C ring chair-like and boat-like conformations using B3LYP/6-31G** and SM5.4/A to estimate aqueous solvation free energy. The results were compared to experimental opioid receptor binding affinities. The total energy difference between ß conformers correlated well with MOR binding affinity, while the aqueous solvation free energy correlated well with the KOR binding affinity.

Effect of surface binding on heterogeneous DNA melting equilibria: a Monte Carlo simulation study.

Deoxyribonucleic acid (DNA) microarrays are constructed with a surface-immobilized single-stranded probe sequence that hydrogen bonds with its complementary target strand from solution and is subsequently detected, making their hybridization equilibrium of central importance. Unexpectedly, the effect of surface immobilization is that if the sequences of probe and target are exchanged, the hybridization equilibrium shifts. Here, configurational-bias Monte Carlo simulations using a coarse-grained model for DNA were carried out for an undecamer double helix both in solution and bound to a surface to determine dissociation equilibria. Four possible surface binding orientations were independently investigated. Analysis shows that the effect of surface binding is to destabilize hydrogen-bonding interactions of bases proximal to the binding site and enhance those of distal bases due to the double helix lying flat on the surface. Results have implications for predicting surface-bound DNA hybridization equilibria.

In vitro identification and verification of inflammatory biomarkers in swine.

Currently there are no non-steroidal anti-inflammatory drugs (NSAIDs) approved for the control of inflammation in swine due to a lack of validated animal models and suitable biomarkers to assess drug efficacy. This study investigates the differential expression of genes altered in response to Escherichia coli lipopolysaccharide (LPS) induced inflammation which may serve as indicators of NSAID efficacy. Unstimulated whole blood from swine was mixed with tissue culture media, stimulated with LPS, and RNA extracted at the following time points 0h, 1h, 3h, 24h and 48h. Total RNA was extracted and analyzed using a commercial swine DNA microarray. The DNA microarray was utilized as a screen to determine potential biomarkers, focusing on the genes that exhibited the greatest degree of differential expression. A master list of 57 genes was formed based on the differential expression as a result of the stimulation. Following analysis, 12 genes whose expressions were significantly altered (8 up- and 4 down-regulated) were chosen for verification via quantitative RT-PCR (qRT-PCR). The qRT-PCR analysis confirmed the differential expression of 11 of the 12 genes chosen via the microarray analyses. Specifically, traditional genes such as SAA, G-CSF, and IL-10 were up-regulated, while CD4 was down-regulated; all of the genes were altered by 24h or 48h post-stimulation. We demonstrate here that expression of these 11 genes is altered as a direct result of LPS stimulation and consequently inflammation.