Practitioners' Dilemmas and Strategies in Decision-Making Conversations Where Patients and Companions Take Divergent Positions on a Healthcare Measure: An Observational Study Using Conversation Analysis.

The presence of companions adds complexity to healthcare interactions. Few studies have characterized challenges arising when interactions involve healthcare professionals (HCPs), patients, and companions, or how those challenges are managed. Using conversation analysis, we examined recorded episodes where patients and companions adopt divergent positions on healthcare measures (e.

Disagreement between two common biomarkers of global DNA methylation.

Background: The quantification of global DNA methylation has been established in epigenetic screening. As more practicable alternatives to the HPLC-based gold standard, the methylation analysis of CpG islands in repeatable elements (LINE-1) and the luminometric methylation assay (LUMA) of overall 5-methylcytosine content in "CCGG" recognition sites are most widely used. Both methods are applied as virtually equivalent, despite the hints that their results only partly agree.

Emergent biomarker derived from next-generation sequencing to identify pain patients requiring uncommonly high opioid doses.

Next-generation sequencing (NGS) provides unrestricted access to the genome, but it produces 'big data' exceeding in amount and complexity the classical analytical approaches. We introduce a bioinformatics-based classifying biomarker that uses emergent properties in genetics to separate pain patients requiring extremely high opioid doses from controls. Following precisely calculated selection of the 34 most informative markers in the OPRM1, OPRK1, OPRD1 and SIGMAR1 genes, pattern of genotypes belonging to either patient group could be derived using a k-nearest neighbor (kNN) classifier that provided a diagnostic accuracy of 80.

Methadone induces hypermethylation of human DNA.

Background: Increased global DNA methylation in the blood of patients chronically exposed to opioids had been interpreted as an indication of an epigenetic action of this drug class.

Materials & Methods: To strengthen the causality, human MCF7 cells were cultured in media with the addition of several known or potential modulators of DNA methylation including methadone.

Results: Following 3 days of incubation with several different known or potential epigenetic modulators, global DNA methylation, quantified at LINE-1 CpG islands, showed a large variability across all treatments ranging from 27.

Cytochrome P450 epoxygenase dependence of opioid analgesia: fluconazole does not interfere with remifentanil-mediated analgesia in human subjects.

Cytochrome P450 (CYP) inhibitors may reduce opioid analgesia by inhibiting CYP activity-dependent post-opioid receptor signaling pathways in the brain. This suggestion was predicated on observations of highly attenuated morphine antinociception in rodents after intracerebroventricular injection of fluconazole or carrying a neuron-specific deletion of the cytochrome P450 reductase. However, based on assessments of thermal and electrical pain tolerance, respiratory function, and side effects in 21 healthy volunteers, before and during steady-state concentrations of 1.

Consequences of a human TRPA1 genetic variant on the perception of nociceptive and olfactory stimuli.

Background: TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity.

Methods: Olfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G>A, a variant known to enhance cold pain perception.

µ-opioid receptor gene variant OPRM1 118 A>G: a summary of its molecular and clinical consequences for pain.

The human µ-opioid receptor variant 118 A>G (rs1799971) has become one of the most analyzed genetic variants in the pain field. At the molecular level, the variant reduces opioid receptor signaling efficiency and expression, the latter probably via a genetic-epigenetic interaction. In experimental settings, the variant was reproducibly associated with decreased effects of exogenous opioids.

Common non-epigenetic drugs as epigenetic modulators.

Epigenetic effects are exerted by a variety of factors and evidence increases that common drugs such as opioids, cannabinoids, valproic acid, or cytostatics may induce alterations in DNA methylation patterns or histone conformations. These effects occur via chemical structural interactions with epigenetic enzymes, through interactions with DNA repair mechanisms. Computational predictions indicate that one-twentieth of all drugs might potentially interact with human histone deacetylase, which was prospectively experimentally verified for the compound with the highest predicted interaction probability.

Functional genomics suggest neurogenesis in the adult human olfactory bulb.

The human olfactory bulb displays high morphologic dynamics changing its volume with olfactory function, which has been explained by active neurogenetic processes. Discussion continues whether the human olfactory bulb hosts a continuous turnover of neurons. We analyzed the transcriptome via RNA quantification of adult human olfactory bulbs and intersected the set of expressed transcriptomic genes with independently available proteomic expression data.

Linkage between increased nociception and olfaction via a SCN9A haplotype.

Background And Aims: Mutations reducing the function of Nav1.7 sodium channels entail diminished pain perception and olfactory acuity, suggesting a link between nociception and olfaction at ion channel level. We hypothesized that if such link exists, it should work in both directions and gain-of-function Nav1.

Functional genomics of pain in analgesic drug development and therapy.

Advances in genomic research have led to the clarification of the detailed involvement of gene products in biological pathways and these are being increasingly exploited in strategies for drug discovery and repurposing. Concomitant developments in informatics have resulted in the acquisition of complex gene information through the application of computational analysis of molecular interaction networks. This approach enables the acquired knowledge on hundreds of genes to be used to view molecular disease mechanisms from a genetic point of view.

Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain.

Environmentally caused changes in chromosomes that do not alter the DNA sequence but cause phenotypic changes by altering gene transcription are summarized as epigenetics. A major epigenetic mechanism is methylation or demethylation at CpG-rich DNA islands. DNA methylation triggered by drugs has largely unexplored therapeutic consequences.

Necessity and risks of arterial blood sampling in healthy volunteer studies.

Arterial blood sampling is necessary when drugs such as the fast-acting opioid analgesic remifentanil exhibit relevant differences between arterial and venous blood concentrations. Arterial cannulation is generally considered to be clinically safe and has thus become a standard procedure in pharmacokinetic-pharmacodynamic assessments. However, rare cases of arterial occlusions have to be considered in risk-benefit assessments of arterial sampling in pharmacokinetic studies, especially when including healthy volunteers.

Kinetics of serum brain-derived neurotrophic factor following low-intensity versus high-intensity exercise in men and women.

Physical activity has been shown to enhance circulating brain-derived neurotrophic factor (BDNF) in animals and humans. However, the exact time course and sex-specific modulation of peripheral BDNF in response to exercise are still poorly understood. We examined the kinetics of BDNF serum concentrations in response to perceived high-intensity and low-intensity exercise, and during a subsequent recovery period by taking several blood samples during each phase.

Genetic-epigenetic interaction modulates μ-opioid receptor regulation.

Genetic and epigenetic mechanisms play important roles in protein expression, although at different levels. Genetic variations can alter CpG sites and thus influence the epigenetic regulation of mRNA expression, providing an increasingly recognized mechanism of functional consequences of genetic polymorphisms. One of those genetic effects is the association of reduced μ-opioid receptor expression with the functional genetic variant N40D (OPRM1 118A>G, rs1799971) that causes an amino acid exchange in the extracellular terminal of the μ-opioid receptor.

A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers.

Background And Aims: Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection.

Single and combined IL28B, ITPA and SLC28A3 host genetic markers modulating response to anti-hepatitis C therapy.

Advances in hepatitis C pharmacogenomics identified modulations of a sustained virologic response (SVR) by frequent IL28B gene variants and of ribavirin-induced hemolysis by frequent ITPA gene variants. These associations have been widely reproduced in various ethnicities, clinical settings and hepatitis C viral genotypes. The IL28B minor alleles rs8099917G, rs12979860T and rs12980275G have been associated with non-SVR whereas the ITPA minor alleles rs1127354A and rs7270101C were associated with less hemolytic side effects, an effect also attributed to a nucleoside transporter gene SLC28A3 rs10868138G/rs56350726T haplotype.

Trails and physical activity: a review.

Purpose: To provide a synthesis of research on trails and physical activity from the public health, leisure sciences, urban planning, and transportation literatures.

Methods: A search of databases was conducted to identify studies published between 1980 and 2008.

Results: 52 studies were identified.

Effect sizes in experimental pain produced by gender, genetic variants and sensitization procedures.

Background: Various effects on pain have been reported with respect to their statistical significance, but a standardized measure of effect size has been rarely added. Such a measure would ease comparison of the magnitude of the effects across studies, for example the effect of gender on heat pain with the effect of a genetic variant on pressure pain.

Methodology/principal Findings: Effect sizes on pain thresholds to stimuli consisting of heat, cold, blunt pressure, punctuate pressure and electrical current, administered to 125 subjects, were analyzed for 29 common variants in eight human genes reportedly modulating pain, gender and sensitization procedures using capsaicin or menthol.

Role of nucleoside transporters SLC28A2/3 and SLC29A1/2 genetics in ribavirin therapy: protection against anemia in patients with chronic hepatitis C.

Background And Aim: The standard of hepatitis C antiviral therapy combines pegylated interferon-α with ribavirin. This polar guanosine analog improves the sustained virological response (SVR) rates, but may induce hemolytic anemia. As its pharmacokinetics depend on facilitated transmembrane transport, we assessed whether variants in genes that code for concentrative (concentrative nucleoside transporters 2 and 3 coded by SLC28A2 and SLC28A3, respectively) and equilibrative nucleoside transporters (equilibrative nucleoside transporters 1 and 2 coded by SLC29A1 and SLC29A2, respectively) are associated with the therapy response and side effects.

Screening for IL28B gene variants identifies predictors of hepatitis C therapy success.

Background: Recent research has shown that genetic variation in the IL28B gene predicts both chronicity of HCV infection and sustained virological response (SVR) to antiviral standard therapy. Because HCV affects 170 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma, screening for prognostic factors in routine clinical practice requires rapid and reliable assays.

Methods: The frequencies of gene polymorphisms IL28B rs8099917, rs12979860 and rs12980275 were investigated in two cohorts of 89 and 187 unrelated HCV-infected Caucasian patients and 195 non-infected participants.

Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.

Background & Aims: Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection.

Methods: Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin.

Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients.

Background & Aims: Genetic variation in the interleukin 28B (IL28B) gene has been associated with the response to interferon-alfa/ribavirin therapy in hepatitis C virus (HCV) genotype 1-infected patients. The importance of three IL28B single nucleotide polymorphisms (rs8099917, rs12980275 and rs12979860) for HCV genotype 2/3-infected patients is unknown.

Methods: In patients with chronic hepatitis C genotype 2/3 (n=267), IL28B host genotypes (rs8099917, rs12980275 and rs12979860) were analyzed for associations with sustained virologic response (SVR) to antiviral therapy with (pegylated) interferon-alfa and ribavirin and with respect to epidemiological, biochemical, and virological parameters.

Epigenetics in pain and analgesia: an imminent research field.

Heritable phenotypes resulting from environment-caused changes in a chromosome without alterations in the DNA sequence are increasingly recognized as a basis of personalized therapy. Epigenetic mechanisms include covalent modifications of the DNA (methylation) or of the DNA-packaging histones (e.g.

A KCNJ6 (Kir3.2, GIRK2) gene polymorphism modulates opioid effects on analgesia and addiction but not on pupil size.

Aim: KCNJ6 coding for potassium inwardly rectifying channels (Kir3.2, GIRK2) is important for opioid receptor transmission. The KCNJ6 rs2070995 AA genotype has been associated with increased opioid analgesic requirements in Japanese.