Bronchial mucosal inflammation and illness severity in response to experimental rhinovirus infection in COPD.

BACKGROUND: Respiratory viral infection causes chronic obstructive pulmonary disease (COPD) exacerbations. We previously reported increased bronchial mucosa eosinophil and neutrophil inflammation in patients with COPD experiencing naturally occurring exacerbations. But it is unclear whether virus per se induces bronchial mucosal inflammation, nor whether this relates to exacerbation severity. OBJECTIVES: We sought to determine the extent and nature of bronchial mucosal inflammation following experimental rhinovirus (RV)-16-induced COPD exacerbations and its relationship to disease severity. METHODS: Bronchial mucosal inflammatory cell phenotypes were determined at preinfection baseline and following experimental RV infection in 17 Global Initiative for Chronic Obstructive Lung Disease stage II subjects with COPD and as controls 20 smokers and 11 nonsmokers with normal lung function. No subject had a history of asthma/allergic rhinitis: all had negative results for aeroallergen skin prick tests. RESULTS: RV infection increased the numbers of bronchial mucosal eosinophils and neutrophils only in COPD and CD8+ T lymphocytes in patients with COPD and nonsmokers. Monocytes/macrophages, CD4+ T lymphocytes, and CD20+ B lymphocytes were increased in all subjects. At baseline, compared with nonsmokers, subjects with COPD and smokers had increased numbers of bronchial mucosal monocytes/macrophages and CD8+ T lymphocytes but fewer numbers of CD4+ T lymphocytes and CD20+ B lymphocytes. The virus-induced inflammatory cells in patients with COPD were positively associated with virus load, illness severity, and reductions in lung function. CONCLUSIONS: Experimental RV infection induces bronchial mucosal eosinophilia and neutrophilia only in patients with COPD and monocytes/macrophages and lymphocytes in both patients with COPD and control subjects. The virus-induced inflammatory cell phenotypes observed in COPD positively related to virus load and illness severity. Antiviral/anti-inflammatory therapies could attenuate bronchial inflammation and ameliorate virus-induced COPD exacerbations.

Measurement Properties of the SF-MPQ-2 Neuropathic Qualities Subscale in Persons with CRPS: Validity, Responsiveness, and Rasch Analysis.

OBJECTIVES: The purpose of this study was to conduct classical psychometric evaluation and Rasch analysis on the Neuropathic Qualities subscale of the Short-Form McGill Pain Questionnaire-2 utilizing scores from persons with complex regional pain syndrome to consider reliability and person separation, validity (including unidimensionality), and responsiveness in this population. METHODS: Secondary analysis of longitudinal data from persons with acute complex regional pain syndrome was utilized for analysis of the psychometric properties and fit to the Rasch model of the Neuropathic Qualities subscale. We followed an iterative process of Rasch analysis to evaluate and address data fitting challenges. RESULTS: Repeated measures from 59 persons meeting the Budapest criteria were used for analysis. Both item-total correlations and unidimensionality analyses supported theoretical construct validity; all convergent construct validity hypotheses were also supported. Responsiveness was demonstrated comparing baseline and one-year data at d = 0.92, with a standardized response mean of 0.97. Data were able to fit the Rasch model, but all Neuropathic Qualities items had disordered thresholds that required rescoring. Additionally, local dependency and differential item function were addressed by "bundling," suggesting that no further item reduction would be possible. CONCLUSIONS: This study provided preliminary support for the validity and responsiveness of the Neuropathic Qualities subscale in persons with complex regional pain syndrome. Rasch analysis further endorses use of the Neuropathic Qualities subscale as a "stand-alone" measure for neuropathic features, but with substantial background data transformations. Replication with larger samples is recommended to increase confidence in these findings.

Does Kindness Matter? Diabetes, Depression, and Self-Compassion: A Selective Review and Research Agenda.

Depression and severe psychological distress are frequently comorbid with diabetes and are associated with reduced adherence to medication and healthy lifestyle regimens, poorer glycemic control, and increased complications. The mixed success of existing treatments for depression in diabetes patients suggests a need for supplementary approaches to this common problem. This article reviews recent evidence for the benefits of self-compassion in chronically ill patients, suggesting its utility as a clinical tool for improving self-care, depression, and glycemic control in diabetes. Possible physical and psychological pathways by which self-compassion may promote better outcomes in diabetes patients are considered, with particular attention given to reductions in negative self-judgment and improved motivation to undertake self-care.

Induction of regulator of G-protein signaling 2 expression by long-acting ß2-adrenoceptor agonists and glucocorticoids in human airway epithelial cells.

In asthma and chronic obstructive pulmonary disease (COPD) multiple mediators act on Gαq-linked G-protein-coupled receptors (GPCRs) to cause bronchoconstriction. However, acting on the airway epithelium, such mediators may also elicit inflammatory responses. In human bronchial epithelial BEAS-2B cells (bronchial epithelium + adenovirus 12-SV40 hybrid), regulator of G-protein signaling (RGS) 2 mRNA and protein were synergistically induced in response to combinations of long-acting ß2-adrenoceptor agonist (LABA) (salmeterol, formoterol) plus glucocorticoid (dexamethasone, fluticasone propionate, budesonide). Equivalent responses occurred in primary human bronchial epithelial cells. Concentrations of glucocorticoid plus LABA required to induce RGS2 expression in BEAS-2B cells were consistent with the levels achieved therapeutically in the lungs. As RGS2 is a GTPase-activating protein that switches off Gαq, intracellular free calcium ([Ca(2+)]i) flux was used as a surrogate of responses induced by histamine, methacholine, and the thromboxane receptor agonist U46619 [(Z)-7-[(1S,4R,5R,6S)-5-[(E,3S)-3-hydroxyoct-1-enyl]-3-oxabicyclo[2.2.1]heptan-6-yl]hept-5-enoic acid]. This was significantly attenuated by salmeterol plus dexamethasone pretreatment, or RGS2 overexpression, and the protective effect of salmeterol plus dexamethasone was abolished by RGS2 RNA silencing. Although methacholine and U46619 induced interleukin-8 (IL-8) release and this was inhibited by RGS2 overexpression, the repression of U46619-induced IL-8 release by salmeterol plus dexamethasone was unaffected by RGS2 knockdown. Given a role for Gαq-mediated pathways in inducing IL-8 release, we propose that RGS2 acts redundantly with other effector processes to repress IL-8 expression. Thus, RGS2 expression is a novel effector mechanism in the airway epithelium that is induced by glucocorticoid/LABA combinations. This could contribute to the efficacy of glucocorticoid/LABA combinations in asthma and COPD.

Why do older people oppose physician-assisted dying? A qualitative study.

BACKGROUND: Physician-assisted dying at the end of life has become a significant issue of public discussion. While legally available in a number of countries and jurisdictions, it remains controversial and illegal in New Zealand. AIM: The study aimed to explore the reasons some healthy older New Zealanders oppose physician-assisted dying in order to inform current debate. DESIGN: Recorded interviews were transcribed and analysed by the authors after some edits had been made by respondents. SETTING/PARTICIPANTS: In all, 11 older participants (over 65 years) who responded to advertisements placed in Grey Power magazines and a University of Auckland email list were interviewed for around 1 h and asked a number of open-ended questions. RESULTS: Four central themes opposing physician-assisted dying were identified from the interviews: one's personal experience with health care and dying and death, religious reasoning and beliefs, slippery slope worries and concern about potential abuses if physician-assisted dying were legalised. CONCLUSIONS: An important finding of the study suggests that how some older individuals think about physician-assisted dying is strongly influenced by their past experiences of dying and death. While some participants had witnessed good, well-managed dying and death experiences which confirmed for them the view that physician-assisted dying was unnecessary, those who had witnessed poor dying and death experiences opposed physician-assisted dying on the grounds that such practices could come to be abused by others.

ß2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids.

In asthma and chronic obstructive pulmonary disease, activation of G(q)-protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting ß(2)-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G(q) signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases.

Inhaled long-acting ß2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD.

BACKGROUND: Combination inhaled therapy with long-acting ß2 agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain. METHODS: Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 µg, FP 500 µg, salmeterol xinafoate (SLM) 50 µg, and combination FP 100 µg + SLM 50 µg. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR-glucocorticoid response element ELISA-based assay. RESULTS: Nuclear GR significantly increased after the inhalation of FP 500 µg (P < .01), but not after the inhalation of FP 100 µg or SLM 50 µg, compared with placebo. Interestingly, SLM in combination with FP 100 µg increased nuclear GR levels equivalent to those of FP 500 µg alone. This was significantly greater than either FP 100 µg (P < .05) or SLM 50 µg (P < .01) alone. In vitro in a human macrophage cell line, SLM (10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 ± 0.6 vs 8.4 ± 1.1 × 10(-6) copies, P < .05) and 2 × glucocorticoid response element-luciferase reporter gene activity (250.1 ± 15.6 vs 103.1 ± 23.6-fold induction, P < .001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1ß-induced CXCL8 (P < .05). CONCLUSIONS: Addition of SLM 50 µg to FP 100 µg enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD.

Neutrophil adhesion molecules in experimental rhinovirus infection in COPD.

BACKGROUND: COPD exacerbations are associated with neutrophilic airway inflammation. Adhesion molecules on the surface of neutrophils may play a key role in their movement from blood to the airways. We analysed adhesion molecule expression on blood and sputum neutrophils from COPD subjects and non-obstructed smokers during experimental rhinovirus infections. METHODS: Blood and sputum were collected from 9 COPD subjects and 10 smoking and age-matched control subjects at baseline, and neutrophil expression of the adhesion molecules and activation markers measured using flow cytometry. The markers examined were CD62L and CD162 (mediating initial steps of neutrophil rolling and capture), CD11a and CD11b (required for firm neutrophil adhesion), CD31 and CD54 (involved in neutrophil transmigration through the endothelial monolayer) and CD63 and CD66b (neutrophil activation markers). Subjects were then experimentally infected with rhinovirus-16 and repeat samples collected for neutrophil analysis at post-infection time points. RESULTS: At baseline there were no differences in adhesion molecule expression between the COPD and non-COPD subjects. Expression of CD11a, CD31, CD62L and CD162 was reduced on sputum neutrophils compared to blood neutrophils. Following rhinovirus infection expression of CD11a expression on blood neutrophils was significantly reduced in both subject groups. CD11b, CD62L and CD162 expression was significantly reduced only in the COPD subjects. Blood neutrophil CD11b expression correlated inversely with inflammatory markers and symptom scores in COPD subjects. CONCLUSION: Following rhinovirus infection neutrophils with higher surface expression of adhesion molecules are likely preferentially recruited to the lungs. CD11b may be a key molecule involved in neutrophil trafficking in COPD exacerbations.

Rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with virus (mostly rhinovirus) and bacterial infections, but it is not known whether rhinovirus infections precipitate secondary bacterial infections. OBJECTIVES: To investigate relationships between rhinovirus infection and bacterial infection and the role of antimicrobial peptides in COPD exacerbations. METHODS: We infected subjects with moderate COPD and smokers and nonsmokers with normal lung function with rhinovirus. Induced sputum was collected before and repeatedly after rhinovirus infection and virus and bacterial loads measured with quantitative polymerase chain reaction and culture. The antimicrobial peptides secretory leukoprotease inhibitor (SLPI), elafin, pentraxin, LL-37, α-defensins and ß-defensin-2, and the protease neutrophil elastase were measured in sputum supernatants. MEASUREMENTS AND MAIN RESULTS: After rhinovirus infection, secondary bacterial infection was detected in 60% of subjects with COPD, 9.5% of smokers, and 10% of nonsmokers (P < 0.001). Sputum virus load peaked on Days 5-9 and bacterial load on Day 15. Sputum neutrophil elastase was significantly increased and SLPI and elafin significantly reduced after rhinovirus infection exclusively in subjects with COPD with secondary bacterial infections, and SLPI and elafin levels correlated inversely with bacterial load. CONCLUSIONS: Rhinovirus infections are frequently followed by secondary bacterial infections in COPD and cleavage of the antimicrobial peptides SLPI and elafin by virus-induced neutrophil elastase may precipitate these secondary bacterial infections. Therapy targeting neutrophil elastase or enhancing innate immunity may be useful novel therapies for prevention of secondary bacterial infections in virus-induced COPD exacerbations.

End-of-life care in nursing and care homes.

BACKGROUND: More than 70,000 people die each year in nursing and residential care homes, yet comparatively little attention has been paid to end-of-life care practice and its challenges in this setting. METHOD AND RESULTS: We conducted interviews and group discussions in 12 homes, involving 73 residents, 97 members of staff and 16 relatives. These revealed that personalised care, dignity and respect, making time, talking about death, relatives' roles, and staff support were priorities for all concerned. CONCLUSIONS: Training is vital in helping staff to engage sensitively, respectfully and creatively with dying residents. Staffing levels must be sufficient so staff can sit with residents and care in a way that is attuned to their personality, life history and wishes. relatives help to ensure a "civilised death".

Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation.

RATIONALE: Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations. OBJECTIVES: To evaluate experimental rhinovirus infection as a model of COPD exacerbation and to investigate the mechanisms of virus-induced exacerbations. METHODS: We used experimental rhinovirus infection in 13 subjects with COPD and 13 nonobstructed control subjects to investigate clinical, physiologic, pathologic, and antiviral responses and relationships between virus load and these outcomes. MEASUREMENTS AND MAIN RESULTS: Clinical data; inflammatory mediators in blood, sputum, and bronchoalveolar lavage; and viral load in nasal lavage, sputum, and bronchoalveolar lavage were measured at baseline and after infection with rhinovirus 16. After rhinovirus infection subjects with COPD developed lower respiratory symptoms, airflow obstruction, and systemic and airway inflammation that were greater and more prolonged compared with the control group. Neutrophil markers in sputum related to clinical outcomes and virus load correlated with inflammatory markers. Virus load was higher and IFN production by bronchoalveolar lavage cells was impaired in the subjects with COPD. CONCLUSIONS: We have developed a new model of COPD exacerbation that strongly supports a causal relationship between rhinovirus infection and COPD exacerbations. Impaired IFN production and neutrophilic inflammation may be important mechanisms in virus-induced COPD exacerbations.

The benefits of Q + PPGIS for coupled human-natural systems research: A systematic review.

Managing complex problems in socio-ecological systems (SES) requires innovative approaches, which account for multiple scales, large datasets, and diverse lived experiences. By combining two commonly utilized mixed-methods, public participation GIS (PPGIS) and Q-method (Q), Q + PPGIS has the potential to reveal competing agendas and reduce conflict, but its benefits and weaknesses are comparatively understudied. Using a systematic review, we evaluated how different studies have employed and implemented the Q + PPGIS method. We found 16 studies, comprising 30 publications, with considerable variation in their geographic foci, research disciplines, and addressed SES challenges. These studies exhibit a lack of cohesion between methodological design and implementation and the absence of a consistent application of the method. Nonetheless, Q + PPGIS offers a tool that can guide policy, better inform stakeholders, and reduce conflict based on misconceptions. Resolving the shortcomings identified here will broaden Q + PPGIS utility in geographically situating and representing multiple realities within complex socio-ecological systems challenges.

Cilomilast counteracts the effects of cigarette smoke in airway epithelial cells.

Cigarette smoke extracts (CSE) alter TLR4 expression and activation in bronchial epithelial cells. Cilomilast, a phosphodiesterase-4 inhibitor, inhibits cigarette smoke-induced neutrophilia. This study was aimed to explore whether cilomilast, in a human bronchial epithelial cell line (16-HBE), counteracted CSE effects. In particular, TLR4 expression, IP-10 and IL-8 release, lymphocyte and neutrophil chemotactic activity and ERK and IkBa phosphorylation in CSE and LPS-stimulated 16-HBE were assessed. CSE increased TLR4 expression, reduced IP-10 release and lymphocyte chemotactic activity and increased IL-8 release and neutrophil chemotactic activity. Cilomilast reduced TLR4 expression, IL-8 release and neutrophil chemotactic activity as well as it increased IP-10 release and lymphocyte chemotactic activity. All these cilomilast mediated effects were associated with a reduced ERK1/2 and with an increased IkBa phosphorylation. In conclusion, the present study provides compelling evidences that cilomilast may be considered a possible valid therapeutic option in controlling inflammatory processes present in smokers.

Pre-sleep cognitive arousal exacerbates sleep disturbance in chronic pain: an exploratory daily diary and actigraphy study.

OBJECTIVES: Insomnia is commonly comorbid with chronic pain, and typically leads to worse outcomes. Two factors that could contribute to a cycle of pain and sleeplessness are pre-sleep cognitive arousal (repetitive thought processes) and low mood. This study aimed to examine how pain, sleep disturbance, mood, and pre-sleep cognitive arousal inter-relate, to determine whether low mood or pre-sleep cognitive arousal contribute to a vicious cycle of pain and insomnia. METHODS: Forty seven chronic pain patients completed twice daily diary measures and actigraphy for one week. Analyses investigated the temporal and directional relationships between pain intensity, sleep quality, time awake after sleep onset, anhedonic and dysphoric mood, and pre-sleep cognitive arousal. Fluctuations in predictor variables were used to predict outcome variables the following morning using mixed-effects modelling. RESULTS: For people with chronic pain, an evening with greater pre-sleep cognitive arousal (relative to normal) led to a night of poorer sleep (measured objectively and subjectively), lower mood in the morning, and a greater misperception of sleep (underestimating sleep). A night of poorer sleep quality led to greater pain the following morning. Fluctuations in pain intensity and depression did not have a significant influence on subsequent sleep. CONCLUSIONS: For people with chronic pain, cognitive arousal may be a key variable exacerbating insomnia, which in turn heightens pain. Future studies could target cognitive arousal to assess effects on sleep and pain outcomes.

Long acting beta2-agonist and corticosteroid restore airway glandular cell function altered by bacterial supernatant.

BACKGROUND: Staphylococcus aureus releases virulence factors (VF) that may impair the innate protective functions of airway cells. The aim of this study was to determine whether a long-acting beta2 adrenergic receptor agonist (salmeterol hydroxynaphthoate, Sal) combined with a corticosteroid (fluticasone propionate, FP) was able to regulate ion content and cytokine expression by airway glandular cells after exposure to S. aureus supernatant. METHODS: A human airway glandular cell line was incubated with S. aureus supernatant for 1 h and then treated with the combination Sal/FP for 4 h. The expression of actin and CFTR proteins was analyzed by immunofluorescence. Videomicroscopy was used to evaluate chloride secretion and X-ray microanalysis to measure the intracellular ion and water content. The pro-inflammatory cytokine expression was assessed by RT-PCR and ELISA. RESULTS: When the cells were incubated with S. aureus supernatant and then with Sal/FP, the cellular localisation of CFTR was apical compared to the cytoplasmic localisation in cells incubated with S. aureus supernatant alone. The incubation of airway epithelial cells with S. aureus supernatant reduced by 66% the chloride efflux that was fully restored by Sal/FP treatment. We also observed that Sal/FP treatment induced the restoration of ion (Cl and S) and water content within the intracellular secretory granules of airway glandular cells and reduced the bacterial supernatant-dependent increase of pro-inflammatory cytokines IL8 and TNFalpha. CONCLUSIONS: Our results demonstrate that treatment with the combination of a corticosteroid and a long-acting beta2 adrenergic receptor agonist after bacterial infection restores the airway glandular cell function. Abnormal mucus induced by defective ion transport during pulmonary infection could benefit from treatment with a combination of beta2 adrenergic receptor agonist and glucocorticoid.

Salmeterol with fluticasone enhances the suppression of IL-8 release and increases the translocation of glucocorticoid receptor by human neutrophils stimulated with cigarette smoke.

The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used in chronic obstructive pulmonary disease (COPD). Recently, we have demonstrated that combination of salmeterol and fluticasone propionate (FP) additionally suppress the production of IL-8 by human monocyte. In this study, the molecular mechanism behind the effectiveness of this combination therapy is investigated in human neutrophils. Human neutrophils were preincubated with salmeterol or FP or the combination. The amount of interleukin-8 (IL-8), elastase and matrix metalloproteinases (MMP)-2 and -9 releases, and reactive oxygen species (ROS) generation and expression of MAP kinase phosphatase (MKP-1) and glucocorticoid receptor (GR) were determined. Cigarette smoke medium (CSM) induces an increased expression of CXC receptors and the production of ROS that may explain the strong production of IL-8 by neutrophils. The expression of CXC receptors, the production of ROS, and the release of elastase and MMP-2 and -9 were not influenced by salmeterol, FP, or the combination. Interestingly, the combination therapy had an additive suppressive effect on the CSM-induced production of IL-8. The latter could be explained by an increased mRNA expression of MKP-1, the GR and an increased translocation of the GR to the nucleus. This leads eventually to suppression of both the NF-kappaB and MAPK pathways and, hence, to less IL-8 production by the neutrophil. These data are in support for the use of a combination therapy in COPD patients.

Evaluating Commonalities Across Medically Unexplained Symptoms.

This commentary presents commonalities in medically unexplained symptoms (MUS) across multiple organ systems, including symptoms, aetiological mechanisms, comorbidity with mental health disorders, symptom burden and impact on quality of life. Further, treatment outcomes and barriers in the clinician⁻patient relationship, and cross-cultural experiences are highlighted. This discussion is necessary in aiding an improved understanding and management of MUS due to the interconnectedness underlying MUS presentations across the spectrum of medical specialties.

You'd Better Believe It: The Conceptual and Practical Challenges of Assessing Malingering in Patients With Chronic Pain.

Chronic pain is a prevalent and costly condition, with many patients receiving income support and funded treatment. Given that pain cannot be assessed objectively, patients may be suspected of exaggerating their pain and disability to receive additional funding. Although numerous methods of detecting malingering have been suggested, it is unclear whether clinicians can reliably identify malingering in patients with chronic pain. The present focus article was developed to assess the theoretical basis and empirical support for proposed methods of detecting malingering in patients with chronic pain. Five approaches were identified: the evaluation of behavioral signs, effort testing, pen and paper measures, symptom validity tests, and combined methods. An examination of the literature revealed that proposed assessment tools have little theoretical basis or empirical support in patients with chronic pain. Additionally, assessment tools are inconsistent with advances in pain science and scores or observations are likely to be influenced by the typical features of chronic pain, including fear-avoidance and central sensitization. Clinicians should be aware that as yet neither subjective clinical opinions nor clinical detection methods can reliably identify malingering in patients with chronic pain. Perspective: There is interest in the development of assessment tools to detect malingering in patients with chronic pain. An evaluation of methods reveals theoretical and empirical limitations that undermine the usefulness of these approaches. As yet, there is no reliable way for clinicians to identify malingering in patients with chronic pain.

Cigarette smoke increases Toll-like receptor 4 and modifies lipopolysaccharide-mediated responses in airway epithelial cells.

Airway epithelium is emerging as a regulator of innate immune responses to a variety of insults including cigarette smoke. The main goal of this study was to explore the effects of cigarette smoke extracts (CSE) on Toll-like receptor (TLR) expression and activation in a human bronchial epithelial cell line (16-HBE). The CSE increased the expression of TLR4 and the lipopolysaccharide (LPS) binding, the nuclear factor-kappaB (NF-kappaB) activation, the release of interleukin-8 (IL-8) and the chemotactic activity toward neutrophils. It did not induce TLR2 expression or extracellular signal-regulated signal kinase 1/2 (ERK1/2) activation. The LPS increased the expression of TLR4 and induced both NF-kappaB and ERK1/2 activation. The combined exposure of 16-HBE to CSE and LPS was associated with ERK activation rather than NF-kappaB activation and with a further increase of IL-8 release and of chemotactic activity toward neutrophils. Furthermore, CSE decreased the constitutive interferon-inducible protein-10 (IP-10) release and counteracted the effect of LPS in inducing both the IP-10 release and the chemotactic activity toward lymphocytes. In conclusion, cigarette smoke, by altering the expression and the activation of TLR4 via the preferential release of IL-8, may contribute to the accumulation of neutrophils within the airways of smokers.

A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue.

BACKGROUND: The purpose of this study was to assess the efficacy of cognitive behavior therapy (CBT) as a treatment for multiple sclerosis (MS) fatigue. METHODS: A randomized controlled design was used where 72 patients with MS fatigue were randomly assigned to eight weekly sessions of CBT or relaxation training (RT). RT was designed to control for therapist time and attention. Participants were assessed before and after treatment, and at 3 and 6 months posttreatment. The primary outcome was the Fatigue Scale. Secondary outcomes included measures of stress, mood, and fatigue-related impairment. RESULTS: Analysis was by intention-to-treat. A group by time interaction showed that the CBT group reported significantly greater reductions in fatigue across the 8 months compared with the RT group (p < .02). Calculated effect sizes for fatigue from baseline to the end of treatment were 3.03 [95% confidence interval, 2.22-3.68] for the CBT group and 1.83 [95% confidence interval, 1.26-2.34] for the RT group. Results also indicted that both groups showed clinically significant decreases in fatigue defined as fatigue levels equivalent or less than those reported by a non-fatigued healthy comparison group. There were no significant interactions between group and any of the secondary outcome variables, with both groups showing improvements over time on all measures. INTERPRETATION: Both CBT and RT appear to be clinically effective treatments for fatigue in MS patients, although the effects for CBT are greater than those for RT. Even 6 months after treatment, both treatment groups reported levels of fatigue equivalent to those of the healthy comparison group.