Are people good prognosticators of their own pain? An exploration of the relationship between sex-specific pain beliefs and clinical pain evaluation.

BACKGROUND: Under-explored to date are the interacting influences of patient sex on multi-modal evaluation techniques that tap different domains of the pain experience. OBJECTIVES: The primary aim of Study 1 was to explore the accuracy of sex-specific personal pain beliefs in relation to quantitative pain indicators within sexes, and the secondary objective was to compare the accuracy of sex-specific personal pain beliefs in relation to quantitative pain indicators between sexes. The primary objective of Study 2 was to explore the accuracy of sex-specific personal pain beliefs and self-rated pain severity within sexes, and the secondary objective was to compare sex-specific personal pain beliefs and pain severity ratings between sexes. METHODS: A cross-sectional analysis on two datasets was performed (Study 1, n = 50; Study 2, n = 111). For both studies, independent samples t-tests were used to identify differences in clinical pain evaluations based on sex-specific pain beliefs. Receiver Operating Characteristic (ROC) curves were used to compare the predictive accuracy of males and females clinical pain evaluations based on their ability to handle pain. RESULTS: There were no statistically significant differences in clinical pain evaluations based on self-rated pain beliefs in either study. In Study 2, males were descriptively more accurate predictors of their clinical pain evaluations than were females, though none of the between sex comparisons were statistically significant. CONCLUSION: This work highlights the importance of considering all available clinical pain evaluations as one technique is unlikely to represent the patients pain experience.

Integrating the Gut Microbiome and Stress-Diathesis to Explore Post-Trauma Recovery: An Updated Model.

Musculoskeletal conditions of traumatic and non-traumatic origin represent an ongoing health challenge. While the last three decades have seen significant advancement in our understanding of musculoskeletal conditions, the mechanisms of a delayed or lack of recovery are still a mystery. Here, we present an expansion of the integrated stress-diathesis model through the inclusion of the gut microbiome. Connecting the microbiome with known adverse neurobiologic, microbiologic and pathophysiologic sequelae following an injury, trauma or stressful event may help improve our knowledge of the pathogenesis of poor recovery. Such knowledge could provide a foundation for the exploration and development of more effective interventions to prevent the transition from acute to chronic pain.

An Exploration of Blood Marker×Environment Interaction Effects on Pain Severity and Interference Scores in People With Acute Musculoskeletal Trauma.

OBJECTIVES: Explore the moderating effects of psychological or social variables on associations between biomarkers of inflammation/stress and clinical reports of pain. METHODS: This is a cross-sectional exploratory study. Data were drawn from the Systematic Merging of Biology, Mental Health and Environment (SYMBIOME) longitudinal study (clinicaltrials.gov ID no. NCT02711085). Eligible participants were adults who presented to an Urgent Care Centre in Ontario, Canada within 3 weeks of a noncatastrophic musculoskeletal trauma (no surgery or hospitalization). A questionnaire package was given that included the Brief Pain Inventory (capturing pain severity and pain interference) and relevant person-level variables. Blood samples were also drawn for serum analysis of 8 target biomarkers (brain-derived neurotrophic factor, transforming growth factor beta 1 [TGF-ß1], c-reactive protein, tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, IL-10, and cortisol). RESULTS: Employment before trauma (employed for pay/not employed for pay) fully moderated the association between tumor necrosis factor-α and pain severity (∆R2=4.4%). Pre-existing psychopathology (yes/no) fully moderated the association between TGF-ß1 and pain severity (∆R2=8.0%). Sex (male/female) fully moderated the association between c-reactive protein and pain severity (∆R2=6.3%). A pre-existing pain condition (yes/no) was significantly associated with worse pain interference (R2=7.2%), and partially moderated the effect of IL-1ß on pain interference (∆R2=6.9%). Higher peritraumatic life stress significantly explained 8.9% of variance in pain interference alone, and partially moderated the effect of TGF-ß1 on interference (∆R2=4.4%). DISCUSSION: Simple bivariate associations between blood-based markers and clinical symptoms are unlikely to reveal meaningful relationships. However, when stratified by existing person-level or "metadata" variables, an association may exist for at least 1 clinically relevant subgroup.

Latent profile analysis of blood marker phenotypes and their relationships with clinical pain and interference reports in people with acute musculoskeletal trauma.

Background: The prevalence of inadequate treatments for chronic pain has necessitated the search for biological factors that influence the transition to chronicity. Methods: Antecubital blood was drawn from those who experienced acute, noncatastrophic musculoskeletal trauma. Follow-up occurred at 1, 3, 6, and 12 months with the primary outcome being Brief Pain Inventory (BPI) Functional Interference scores. Eight markers were chosen for latent profile analysis: brain-derived neurotrophic factor (BDNF); transforming growth factor-beta 1 (TGF-ß1); C-reactive protein (CRP); tumor necrosis factor-alpha (TNF-α); interleukins (ILs) 1-beta, 6, and 10; and the stress hormone cortisol. Results: Mean age of the 106 participants was 44.6 years and 58.5% were female. The final model indicated a three-class solution that could be adequately described by three of the eight markers: class 1 = low concentration of all markers (33.9% of the sample), class 2 = average concentration of all markers (47.7%), and class 3 = high concentration of BDNF and TGF-ß1 (18.3%). BPI Pain Interference scores captured at both inception and 6-month follow-up were compared across the three groups. Mean scores were significantly higher in class 3 for the BPI Interference subscale at inception (27.0 [SD 16.4] vs. 35.8 [SD 17.3], P = 0.05) and at 6-month follow-up (2.2 [SD 4.8] vs. 7.3 [SD 10.7], P = 0.03) compared to those of the other two classes. Conclusions: Although recovered populations are not significantly different in BDNF and TGF-ß1 levels, those who experience persisting disability are more likely to have moderate to high levels in serum.

Contexte: La prévalence des traitements inadéquats pour la douleur chronique a nécessité la recherche des facteurs biologiques qui influencent le passage à la chronicité.Méthodes: Du sang du pli du coude a été prélevé sur des personnes ayant subi des traumatismes musculo-squelettiques aigus non invalidants. Le suivi a eu lieu à 1, 3, 6 et 12 mois avec les scores d'interférence fonctionnelle du Questionnaire concis de la douleur (QCD) comme résultat principal. Huit marqueurs ont été choisis pour l'analyse du profil latent : le facteur neurotrophique dérivé du cerveau (BDNF); le facteur de croissance transformant-bêta 1 (TGF-ß1); la protéine C-réactive (CRP); le facteur de nécrose tumorale alpha (TNF-a); les interleukines (IL) 1-bêta, 6 et 10; et le cortisol, l'hormone du stress.Résultats: L'âge moyen des 106 participants était de 44,6 ans et 58,5% étaient des femmes. Le modèle final a indiqué une solution à trois classes qui pourrait être correctement décrite par trois des huit marqueurs : classe 1 = faible concentration de tous les marqueurs (33,9 % de l'échantillon), classe 2 = concentration moyenne de tous les marqueurs (47,7 %), et classe 3 = concentration élevée de BDNF et TGF-ß1 (18,3 %). Les scores d'interférence de la douleur BPI relevés à la fois au début et au suivi à 6 mois ont été comparés entre les trois groupes. Les scores moyens étaient significativement plus élevés dans la classe 3 pour la sous-échelle d'interférence BPI au début (27,0 [SD 16,4] comparativement à 35,8 [SD 17,3], p = 0,05) et à 6 mois de suivi (2,2 [SD 4,8] comparativement à 7,3 [SD 10,7], P = 0,03) par rapport à ceux des deux autres classes.Conclusions: Bien que les populations rétablies ne soient pas significativement différentes en ce qui a trait aux niveaux de BDNF et de TGF-ß1, celles qui souffrent d'une incapacité persistante sont plus susceptibles d'avoir des taux sériques modérés à élevés.

Defining pain and interference recovery trajectories after acute non-catastrophic musculoskeletal trauma through growth mixture modeling.

BACKGROUND: Recovery trajectories support early identification of delayed recovery and can inform personalized management or phenotyping of risk profiles in patients. The objective of this study was to investigate the trajectories in pain severity and functional interference following non-catastrophic musculoskeletal (MSK) trauma in an international, mixed injury sample. METHODS: A prospective longitudinal cohort (n = 241) was formed from patients identified within four weeks of trauma, from attendance at emergency or urgent care centres located in London, ON, Canada, or Chicago, IL, USA. Pain interference was measured via the Brief Pain Inventory (London cohort) or the Neck Disability Index (Chicago cohort). Pain severity was captured in both cohorts using the numeric pain rating scale. Growth mixture modeling and RM repeated measures ANOVA approaches identified distinct trajectories of recovery within pain interference and pain severity data. RESULTS: For pain interference, the three trajectories were labeled accordingly: Class 1 = Rapid recovery (lowest intercept, full or near full recovery by 3 months, 32.0% of the sample); Class 2 = Delayed recovery (higher intercept, recovery by 12 months, 26.7% of the sample); Class 3 = Minimal or no recovery (higher intercept, persistently high interference scores at 12 months, 41.3% of the sample). For pain severity, the two trajectories were labeled: Class 1 = Rapid recovery (lower intercept, recovery by 3 months, 81.3% of the sample); and Class 2 = Minimal or no recovery (higher intercept, flat curve, 18.7% of the sample). The "Minimal or No Recovery" trajectory could be predicted by female sex and axial (vs. peripheral) region of trauma with 74.3% accuracy across the 3 classes for the % Interference outcome. For the Pain Severity outcome, only region (axial trauma, 81.3% accuracy) predicted the "Minimal or No Recovery" trajectory. CONCLUSIONS: These results suggest that three meaningful recovery trajectories can be identified in an international, mixed-injury sample when pain interference is the outcome, and two recovery trajectories emerge when pain severity is the outcome. Females in the sample or people who suffered axial injuries (head, neck, or low back) were more likely to be classed in poor outcome trajectories. TRIAL REGISTRATION: National Institutes of Health - clinicaltrials.gov ( NCT02711085 ; Retrospectively registered Mar 17, 2016).

Effects of Ionic Liquid Alkyl Chain Length on Denaturation of Myoglobin by Anionic, Cationic, and Zwitterionic Detergents.

The unique electrochemical properties of ionic liquids (ILs) have motivated their use as solvents for organic synthesis and green energy applications. More recently, their potential in pharmaceutical chemistry has prompted investigation into their effects on biomolecules. There is evidence that some ILs can destabilize proteins via a detergent-like manner; however, the mechanism still remains unknown. Our hypothesis is that if ILs are denaturing proteins via a detergent-like mechanism, detergent-mediated protein unfolding should be enhanced in the presence of ILs. The properties of myoglobin was examined in the presence of a zwitterionic (N,N-dimethyl-N-dodecylglycine betaine (Empigen BB®, EBB)), cationic (tetradecyltrimethylammonium bromide (TTAB)), and anionic (sodium dodecyl sulfate (SDS)) detergent as well as ILs based on alkylated imidazolium chlorides. Protein structure was measured through a combination of absorbance, fluorescence, and circular dichroism (CD) spectroscopy: absorbance and CD were used to monitor heme complexation to myoglobin, and tryptophan fluorescence quenching was used as an indicator for heme dissociation. Notably, the detergents tested did not fully denature the protein but instead resulted in loss of the heme group. At low IL concentrations, heme dissociation remained a traditional, cooperative process; at high concentrations, ILs with increased detergent-like character exhibited a more complex pattern, which is most likely attributable to micellization of the ionic liquids or direct denaturation or heme dissociation induced by the ILs. These trends were consistent across all species of detergents. 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence was further used to characterize micelle formation in aqueous solutions containing detergent and ionic liquid. The dissociation thermodynamics show that EBB- and TTAB-induced dissociation of heme is not significantly impacted by room temperature ionic liquids (RTILs), whereas SDS-induced dissociation is more dramatically impacted by all RTILs examined. Together, these results indicate a complex interaction of detergents, likely based on headgroup charge, and the active component of RTILs to influence heme dissociation and potentially protein denaturation.

Sequence and Dispersity Are Determinants of Photodynamic Antibacterial Activity Exerted by Peptidomimetic Oligo(thiophene)s.

A library of functionalized oligo(thiophene)s with precisely controlled chain length, regioregularity, sequence, and pendant moieties in the side chains was prepared by iterative convergent/divergent organometallic couplings. The cationic and facially amphiphilic structures were designed to mimic the salient physiochemical features of host defense peptides (HDPs) while concurrently exerting a photodynamic mechanism of antibacterial activity. In the dark, the oligothiophenes exert broad-spectrum and rapid bactericidal activity in the micromolar regime, which is the typical range of HDP activity. Under visible light, the antibacterial potency is enhanced by orders of magnitude, leading to potency in the nanomolar concentration range, whereas the toxicity to red blood cells (RBCs) is almost unaffected by the same visible light exposure. We attribute the potent and selective antibacterial activity to a dual mechanism of action that involves bacterial cell binding, combined with reactive oxygen species production in the bound state. Comonomer sequence and chain length dispersity play important roles in dictating the observed biological activities. The most promising candidate compound from a set of screening experiments showed antibacterial activity that is 3 orders of magnitude more potent against bacteria relative to toxicity against RBCs. Importantly, this compound did not induce resistance upon 21 subinhibitory passages, whereas the activity of ciprofloxacin was reduced 32× in the same condition. Cytotoxicity against HeLa cells in vitro is orders of magnitude weaker than antibacterial activity under visible light illumination. Thus, we have established a new class of HDP-mimetic antibacterial compounds with nanomolar activity and cell type selectivity of greater than 1300-fold. These and related compounds may be highly promising candidates in the urgent search for new topical photodynamic antibacterial formulations.

Heme Dissociation from Myoglobin in the Presence of the Zwitterionic Detergent N,N-Dimethyl-N-Dodecylglycine Betaine: Effects of Ionic Liquids.

We have investigated myoglobin protein denaturation using the zwitterionic detergent Empigen BB (EBB, N,N-Dimethyl-N-dodecylglycine betaine). A combination of absorbance, fluorescence, and circular dichroism spectroscopic measurements elucidated the protein denaturation and heme dissociation from myoglobin. The results indicated that Empigen BB was not able to fully denature the myoglobin structure, but apparently can induce the dissociation of the heme group from the protein. This provides a way to estimate the heme binding free energy, ΔGdissociation. As ionic liquids (ILs) have been shown to perturb the myoglobin protein, we have investigated the effects of the ILs 1-butyl-3-methylimidazolium chloride (BMICl), 1-ethyl-3-methylimidazolium acetate (EMIAc), and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIBF4) in aqueous solution on the ΔGdissociation values. Absorbance experiments show the ILs had minimal effect on ΔGdissociation values when compared to controls. Fluorescence and circular dichroism data confirm the ILs have no effect on heme dissociation, demonstrating that low concentrations ILs do not impact the heme dissociation from the protein and do not significantly denature myoglobin on their own or in combination with EBB. These results provide important data for future studies of the mechanism of IL-mediated protein stabilization/destabilization and biocompatibility studies.

Experimental and Mathematical Analyses Relating Circadian Period and Phase of Entrainment in Neurospora crassa.

Circadian rhythms are observed in most organisms on earth and are known to play a major role in successful adaptation to the 24-h cycling environment. Circadian phenotypes are characterized by a free-running period that is observed in constant conditions and an entrained phase that is observed in cyclic conditions. Thus, the relationship between the free-running period and phase of entrainment is of interest. A popular simple rule has been that the entrained phase is the expression of the period in a cycling environment (i.e., that a short period causes an advanced phase and a long period causes a delayed phase). However, there are experimental data that are not explained by this simple relationship, and no systematic study has been done to explore all possible period-phase relationships. Here, we show the existence of stable period-phase relationships that are exceptions to this rule. First, we analyzed period-phase relationships using populations with different degrees of genome complexity. Second, we generated isogenic F1 populations by crossing 14 classical period mutants to the same female and analyzed 2 populations with a short period/delayed phase and a long period/advanced phase. Third, we generated a mathematical model to account for such variable relationships between period and phase. Our analyses support the view that the circadian period of an organism is not the only predictor of the entrained phase.

Purposefulness as a critical factor in functioning, disability and health.

Guided by theoretical frameworks of health and illness such as the International Classification of Functioning, Disability, and Health (ICF), we seek to describe the importance of purposefulness in the context of rehabilitation. We argue that ascribing meaning to life events, particularly changes in health, and acting in a manner that is driven by purpose is a universal characteristic of human beings. The ability to contextualize purposefulness within the broader biopsychosocial model of illness may provide a greater understanding of the relationship of purpose in the process of rehabilitation. We support the notion that purposefulness is an ever-present component throughout our lives and it exists as a convergence of personal factors, past experiences, and our personal narrative. Having a sense of purposefulness and being able to understand the meaning of different aspects of our lives is what allows us to find purpose while experiencing a health condition. More importantly, and in the context of rehabilitation efforts, we believe that if purposefulness can be identified or collectively defined by the individual, then rehabilitation outcomes may be enhanced. In a variety of contexts ranging from disease, aging, severe trauma, and even war, purposefulness and its component elements consistently distinguish themselves as being essential for regaining a sense of direction and facilitating one's response to any health condition.

Effects of nitric oxide and reactive oxygen species on HIF-1α stabilization following clostridium difficile toxin exposure of the Caco-2 epithelial cell line.

BACKGROUND/AIMS: Stabilization of the hypoxia-inducible factor (HIF-1α) is proposed to provide a protective host-response to C. difficile intoxication. Here, we aimed to elucidate whether nitric oxide and/or reactive oxygen species produced during C. difficile toxin exposure could influence HIF-1α stability and initiate protection against epithelial cell damage. METHODS/RESULTS: HIF-1α and inducible nitric oxide synthase (iNOS) proteins were up-regulated whereas factor-inhibiting HIF-1 (FIH-1) protein was down-regulated in Caco-2 epithelial cell monolayers with in vitro toxin exposure. We demonstrate using the biotin-switch assay that the stabilization of HIF-1α protein occurred via iNOS-dependent nitrosylation. Inhibition of iNOS activity by selective inhibitor (1400W) attenuated HIF-1α stabilization and exacerbated toxin-dependent disruptions in Caco-2 monolayer morphology and tight junctional integrity in vitro. Treatment of Caco-2 cell monolayers with N-actylcysteine (NAC), a scavenger of reactive oxygen species (ROS), attenuated toxin-dependent increases in iNOS and HIF-1α protein levels but had no effect on FIH-1 responses. In addition, mice that were exposed to C. difficile toxin in vivo also demonstrated a significant increase in HIF-1α protein and nitrosylation levels. CONCLUSION: Taken together, these data suggest that important synergistic actions exist between nitric oxide and ROS to stabilize HIF-1α and its innate, protective actions in the context of C. difficile toxin-mediated epithelial injury.