Development of the ATAQ-IPF: a tool to assess quality of life in IPF.

BACKGROUND: There is no disease-specific instrument to assess health-related quality of life (HRQL) in patients with idiopathic pulmonary fibrosis (IPF). METHODS: Patients' perspectives were collected to develop domains and items for an IPF-specific HRQL instrument. We used item variance and Rasch analysis to construct the ATAQ-IPF (A Tool to Assess Quality of life in IPF). RESULTS: The ATAQ-IPF version 1 is composed of 74 items comprising 13 domains. All items fit the Rasch model. Domains and the total instrument possess acceptable psychometric characteristics for a multidimensional questionnaire. The pattern of correlations between ATAQ-IPF scores and physiologic variables known to be important in IPF, along with significant differences in ATAQ-IPF scores between subjects using versus those not using supplemental oxygen, support its validity. CONCLUSIONS: Patient-centered and careful statistical methodologies were used to construct the ATAQ-IPF version 1, an IPF-specific HRQL instrument. Simple summation scoring is used to derive individual domain scores as well as a total score. Results support the validity of the ATAQ-IPF, and future studies will build on that validity.

Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia.

Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring < or =5 min after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.

Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses.

Prior exposure to a stressor can potentiate CNS pro-inflammatory immune responses to a peripheral immune challenge. However, the neuroimmune substrate(s) mediating this effect has not been determined. The present investigation examined whether microglia serve as this neuroimmune substrate given that microglia are the primary immune effector cell in the CNS. The effect of inescapable shock (IS) on glial activation (MHC II, CD11b, Iba-1, and GFAP) and regulatory markers (CD200) in vivo, and microglia pro-inflammatory responses (interleukin-1beta; IL-1beta) to lipopolysaccharide (LPS) ex vivo, were assessed in rat hippocampus. IS upregulated the microglia activation marker MHC II 24h post-IS, while the astroglia marker GFAP was unaffected. IS also downregulated the neuronal glycoprotein CD200, which functions to hold microglia in a quiescent state. Moreover, IS potentiated the pro-inflammatory response to LPS ex vivo 24h post-IS in isolated hippocampal microglia. Finally, the behavioral controllability of shock was manipulated and the effect of escapable (controllable) shock was comparable to the effect of IS on hippocampal microglia responses to LPS ex vivo. The present results suggest that stress can activate microglia, thereby sensitizing the pro-inflammatory reactivity of microglia to immunogenic stimuli.