Rheumatoid arthritis-interstitial lung disease-associated mortality.

RATIONALE: Mortality rates from rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are largely unknown. OBJECTIVES: We sought to determine mortality rates from rheumatoid arthritis-associated interstitial lung disease in the United States from 1988 through 2004. METHODS: Using data from the National Center for Health Statistics, we calculated age-adjusted mortality rates from the deaths of persons with rheumatoid arthritis-associated interstitial lung disease, determined the prevalence of interstitial lung disease in all decedents with rheumatoid arthritis, and compared the age and underlying cause of death in these two cohorts of decedents. MEASUREMENTS AND MAIN RESULTS: From 1988 to 2004, there were 39,138,394 deaths in U.S. residents and 162,032 rheumatoid arthritis-associated deaths. Of these deaths, 10,725 (6.6%) met criteria for rheumatoid arthritis-associated interstitial lung. Mortality rates from rheumatoid arthritis fell over the course of this study in both women and men. However, mortality rates from rheumatoid arthritis-associated interstitial lung disease increased 28.3% in women (to 3.1 per million persons in 2004) and declined 12.5% in men (to 1.5 per million persons in 2004). Because the rate of decline in rheumatoid arthritis outpaced rheumatoid arthritis-associated interstitial lung disease in men, the prevalence of rheumatoid arthritis-associated interstitial lung disease increased in both sexes over time. CONCLUSIONS: Clinically significant RA-ILD occurs in nearly 10% of the RA population, and is associated with shortened survival and more severe underlying disease. Whereas overall mortality rates for RA have fallen, those associated with RA-ILD have increased significantly in older age groups.

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.

BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration.

The present study examined the modulating effects of an intrahippocampal injection of interleukin-1beta (IL-1beta) on brain-derived neurotrophic factor (BDNF) mRNA expression 0.5, 2, 4, and 6 h following contextual fear conditioning, a task known to increase BDNF mRNA, in rats. Contextual fear conditioning produced a time-dependent increase in BDNF mRNA that varied by region of hippocampus. IL-1beta blocked or reduced these increases in BDNF mRNA in the CA1, CA2, and dentate gyrus regions of the hippocampus, but had no effect in cortical regions. These data support the idea that IL-1beta-produced memory deficits may be mediated via BDNF mRNA reductions in hippocampus.

Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus.

Prior research has revealed that treatments that elevate the level of the pro-inflammatory cytokine IL-1beta in the brain, if given after training, impair contextual but not auditory-cue fear conditioning. The present experiments add to these finding by showing that, (a) IL-1beta exerts its effect on contextual fear conditioning by impairing consolidation processes that support the storage of the memory representation of the context; (b) the dorsal hippocampus is a critical site for the effect of IL-1beta; (c) the effect of IL-1beta cannot be attributed to its effect on glucocorticoid levels; and (d) IL-1beta injected into dorsal hippocampus either, immediately, 3, or 24 h, but not 48 h, after training produces this impairment. At this time the mechanisms responsible for this impairment are not understood, but may involve late-phase protein synthesis processes associated with LTP, because later consolidation processes are being disrupted.

Assessing dyspnea and its impact on patients with connective tissue disease-related interstitial lung disease.

RATIONALE: Dyspnea is the cardinal symptom in patients with any type of interstitial lung disease (ILD); however, there are limited data on dyspnea among patients with connective tissue disease-related ILD (i.e., CTD-ILD). OBJECTIVES: To explore the utility of two dyspnea instruments (the University of California San Diego Shortness of Breath Questionnaire [UCSD] and the Dyspnea-12 [D-12]) and use their scores to examine the impact of dyspnea on the lives of patients with CTD-ILD. METHODS: Subjects were enrolled from the Autoimmune Lung Database (ALD) at National Jewish Health. Chronbach's alpha was used to assess the internal consistency reliability of the two dyspnea questionnaires. We used the Multi-Dimensional Health Assessment Questionnaire [MDHAQ] as a measure of health status and examined associations between health status and dyspnea by using Pearson product-moment correlation and linear regression. RESULTS: The internal consistency reliability of each of the two dyspnea questionnaires was excellent (alpha=0.9 for each). There were significant correlations between either of the two dyspnea measures and MDHAQ components. While controlling for ILD severity, dyspnea as assessed by the UCSD, was a significant predictor of physical function (p=0.04), psychological well-being (p=0.005), and fatigue (p=0.02); dyspnea as assessed the D-12, was a significant predictor of psychological well-being (p=0.01) and global status (p=0.03). CONCLUSION: Dyspnea significantly affects day-to-day functioning and global well-being in patients with CTD-ILD. The UCSD and D-12 yield meaningful information about these patients that measures of pulmonary physiology cannot. Future studies should examine other performance characteristics of these self-report measures in patients with CTD-ILD.

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.

Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood.

We have previously demonstrated that bacterial infection (Escherichia coli) in neonatal rats is associated with impaired memory in a fear-conditioning task in adulthood. This impairment, however, is only observed if a peripheral immune challenge (lipopolysaccharide; LPS) is administered around the time of learning. We used a brief separation/handling paradigm to determine if the adult memory impairment associated with neonatal-infection could be prevented. Naturally occurring variations in maternal care promote striking variations in offspring cognitive development, and handling paradigms are used to manipulate the quality and quantity of maternal care. Rats were injected on post natal (P) day 4 with E. coli or PBS, and half from each group were handled for 15 min/day from P4 to 20. All rats were then tested in adulthood. Neonatal handling of rats infected as neonates prevented the increase in microglial cell marker reactivity within the hippocampus, and the exaggerated brain IL-1beta production to LPS normally produced by the infection. Thus, these neural processes were now comparable to levels of non-infected PBS controls. Furthermore, handling completely prevented LPS-induced memory impairment in a context-fear task in adult rats infected as neonates. Finally, neonatal handling dramatically improved spatial learning and memory and decreased anxiety in rats treated early with PBS, but had no beneficial effect on these measures in rats infected as neonates. Taken together, these data suggest that maternal care may profoundly influence neuroinflammatory processes in adulthood, and that infection may also prevent maternal care influences on cognition later in life.

Peripheral infection and aging interact to impair hippocampal memory consolidation.

We report that a peripheral injection of Escherichia coli produces both anterograde and retrograde amnesia in 24 month old, but not 3 month old rats for memories that depend on the hippocampus, that is, memory of context, contextual fear, and place learning. The anterograde effect was restricted to measures of long-term memory. Short-term memory was not affected, nor did E. coli produce amnesia for auditory-cue fear conditioning. There were no age related effects on memory in vehicle-treated rats. In addition to these age-related cognitive effects of E.coli, we report that it produced a marked increased in IL-1beta levels in the hippocampus, but not in parietal cortex or serum. These findings support the hypothesis that age is a vulnerability factor that increases the likelihood that an immune challenge will produce a cognitive impairment. It is possible that this cognitive vulnerability is mediated by age-related changes in the glial environment that results in an exaggerated brain pro-inflammatory response to infection.