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Prostanoids and PGE2 in particular have been long viewed as one of the major mediators of inflammation in arthritis. However, experimental data indicate that PGE2 can serve both pro- and anti-inflammatory functions. We have previously shown (Kojima, F. et al. 2008 J. Immunol. 180, 8361-8368) that microsomal prostaglandin E synthase-1 (mPGES-1) deletion, which regulates PGE2 production, resulted in the suppression of collagen-induced arthritis (CIA) in mice. This suppression was attributable, at least in part, to the impaired generation of type II collagen autoantibodies. In order to examine the function of mPGES-1 and PGE2 in a non-autoimmune form of arthritis, we used the collagen antibody-induced arthritis (CAIA) model in mice deficient in mPGES-1, thereby bypassing the engagement of the adaptive immune response in arthritis development. Here we report that mPGES-1 deletion significantly increased CAIA disease severity. The latter was associated with a significant (~3.6) upregulation of neutrophil, but not macrophage, recruitment to the inflamed joints. The lipidomic analysis of the arthritic mouse paws by quantitative liquid chromatography / tandem mass-spectrometry (LC/MS/MS) revealed a dramatic (~59-fold) reduction of PGE2 at the peak of arthritis. Altogether, this study highlights mPGES-1 and its product PGE2 as important negative regulators of neutrophil-mediated inflammation and suggests that specific mPGES-1 inhibitors may have differential effects on different types of inflammation. Furthermore, neutrophil-mediated diseases could be exacerbated by inhibition of mPGES-1.
PMCID: PMC3897272  PMID: 24055573
Nanohybrids; Room-temperature phosphorescence(RTP); Sensor; Rutin
2.  New Insights into the Benefits of Exercise for Muscle Health in Patients with Idiopathic Inflammatory Myositis 
With recommended treatment, a majority with idiopathic inflammatory myopathy (IIM) develop muscle impairment and poor health. Beneficial effects of exercise have been reported on muscle performance, aerobic capacity and health in chronic polymyositis and dermatomyositis and to some extent in active disease and inclusion body myositis (IBM). Importantly, randomized controlled trials (RCTs) indicate that improved health and decreased clinical disease activity could be mediated through increased aerobic capacity. Recently, reports seeking mechanisms underlying effects of exercise in skeletal muscle indicate increased aerobic capacity (i.e. increased mitochondrial capacity and capillary density, reduced lactate levels), activation of genes in aerobic phenotype and muscle growth programs, and down regulation in genes related to inflammation. Altogether, exercise contributes to both systemic and within-muscle adaptations demonstrating that exercise is fundamental to improve muscle performance and health in IIM. There is a need for RCTs to study effects of exercise in active disease and IBM.
PMCID: PMC4133148  PMID: 24879535
Idiopathic inflammatory myopathies; Polymyositis; Dermatomyositis; Inclusion body myositis; Aerobic capacity; Aerobic metabolism; Exercise adaptations
3.  Fibromyalgia is Associated With Altered Skeletal Muscle Characteristics Which May Contribute to Post-Exertional Fatigue in Post-Menopausal Women 
Arthritis and rheumatism  2013;65(2):519-528.
To identify muscle physiological properties that may contribute to post-exertional fatigue and malaise in women with fibromyalgia (FM).
Healthy postmenopausal women with (n=11) and without (n=11) fibromyalgia, age 51–70 years, participated in this study. Physical characteristics along with self-reported questionnaires were evaluated. Strength loss and tissue oxygenation in response to a fatiguing exercise protocol were used to quantify fatigability and the local muscle hemodynamic profile. Muscle biopsies were obtained to assess between-group differences in baseline muscle properties using histochemical, immunohistochemical and electron microscopic analyses.
No significant difference in muscle fatigue in response to exercise was apparent between healthy controls and subjects with FM. However, self-reported fatigue and pain were correlated to prolonged loss of strength following 12-min of recovery in subjects with FM. Although there was no difference in percent SDH positive (type I) and SDH negative (type II) fibers or in mean fiber cross-sectional area between groups, subjects with FM showed greater size variability and altered fiber size distribution. Only in healthy controls, fatigue-resistance was strongly correlated with the size of SDH positive fibers and hemoglobin oxygenation. By contrast, subjects with FM with the highest percentage of SDH positive fibers recovered strength most effectively, which was correlated to capillary density. However, overall, capillary density was lower in subjects with FM.
Peripheral mechanisms i.e. altered muscle fiber size distribution and decreased capillary density may contribute to post-exertional fatigue in subjects with FM. Understanding these defects in fibromyalgic muscle may provide valuable insight for treatment.
PMCID: PMC3558634  PMID: 23124535
4.  Use of NSAIDs in treating patients with arthritis 
Arthritis Research & Therapy  2013;15(Suppl 3):S2.
Patients with rheumatic diseases, including rheumatoid arthritis and osteoarthritis, almost universally describe pain and stiffness as important contributors to reduced health-related quality of life. Of the treatment options available, NSAIDs are the most widely used agents for symptomatic treatment. NSAIDs are effective anti-inflammatory and analgesic drugs by virtue of their ability to inhibit biosynthesis of prostaglandins at the level of the cyclooxygenase enzyme. However, many of the adverse effects of NSAIDs are also related to inhibition of prostaglandin production, making their use problematic in some patient populations. For the clinician, understanding the biology of prostaglandin as it relates to gastrointestinal, renal, and cardiovascular physiology and the pharmacologic properties of specific NSAIDs is key to using these drugs safely. Of particular importance is the recognition of co-morbid conditions and concomitant drugs that may increase the risk of NSAIDs in particular patients. In patients with risk factors for NSAID toxicity, using the lowest dose of a drug with a short half-life only when it is needed is likely to be the safest treatment option. For those patients whose symptoms cannot be managed with intermittent treatment, using protective strategies is essential.
PMCID: PMC3891482  PMID: 24267197
5.  Shunting of prostanoid biosynthesis in microsomal prostaglandin E synthase-1 null embryo fibroblasts: regulatory effects on inducible nitric oxide synthase expression and nitrite synthesis 
Microsomal postaglandin (PG) E synthase (mPGES)-1 is an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin (PG)H2 to PGE2, most prominently in inflammatory conditions. Specific inhibitors of mPGES-1 are not yet available, however, mice with genetic deletion of mPGES-1 have been generated that have given insight into the specific role of mPGES-1 in eicosanoid biosynthesis in vivo and in peritoneal macrophages. We created mouse embryo fibroblast (MEF) cell lines that would facilitate investigation of the effect of mPGES-1 genetic deletion on prostanoid biosynthesis in fibroblast lineage cells and its subsequent effect on the expression of inducible NOS (iNOS) and nitrite biosynthesis using cells derived from mPGES-1 wild-type (WT), heterozygous (Het), and null mice. The results show that genetic deletion of mPGES-1 results in a dramatic decrease in PGE2 production in Het and null MEFs under basal conditions and after stimulation with interleukin (IL)-1β, suggesting that mPGES-1 is critically important for PGE2 production. Furthermore, we show that mPGES-1 gene deletion results in diversion of prostanoid production from PGE2 to 6-keto PGF1α (the stable metabolic product of PGI2; prostacyclin) in a gene dose-dependent manner in Het and null MEFs compared with their WT counterparts, suggesting a shunting phenomenon within the arachidonic acid (AA) metabolic pathway. In addition, we show that mPGES-1 gene deletion and subsequent decrease in PGE2 levels results in a differential induction profile of iNOS and nitrite levels (the stable breakdown product of nitric oxide (NO) in mPGES-1 WT MEFs compared with null MEFs. These results provide important information regarding the therapeutic potential for pharmacologic inhibition of mPGES-1 in inflammatory conditions.—Kapoor, M., Kojima, F., Qian, M., Yang, L., and Crofford, L. J. Shunting of prostanoid biosynthesis in microsomal prostaglandin E synthase-1 null embryo fibroblasts: regulatory effects on inducible nitric oxide synthase expression and nitrite synthesis.
PMCID: PMC4415996  PMID: 17023389
arachidonic acid (AA); cyclooxygenase (COX); L-arginine
6.  Salivary Cortisol and Cold Pain Sensitivity in Female Twins 
There is a dearth of knowledge about the link between cortisol and pain sensitivity.
We examined the association of salivary cortisol with indices of cold pain sensitivity in 198 female twins and explored the role of familial confounding.
Three-day saliva samples were collected for cortisol levels and a cold pressor test was used to collect pain ratings and time to threshold and tolerance. Linear regression modeling with generalized estimating equations examined the overall and within-pair associations.
Lower diurnal variation of cortisol was associated with higher pain ratings at threshold (p = 0.02) and tolerance (p < 0.01). The relationship of diurnal variation with pain ratings at threshold and tolerance was minimally influenced by familial factors (i.e., genetics and common environment).
Understanding the genetic and non-genetic mechanisms underlying the link between HPA axis dysregulation and pain sensitivity may help to prevent chronic pain development and maintenance.
PMCID: PMC3926904  PMID: 23955075
cortisol; pain; cold pressor; genetics; twins
7.  Geographic Variation of Chronic Opioid Use in Fibromyalgia 
Clinical therapeutics  2013;35(3):303-311.
Opioid use for the treatment of chronic nonmalignant pain has increased drastically over the past decade. Although no evidence of efficacy exists supporting the treatment of fibromyalgia (FM) with chronic opioid therapy, a large number of patients are receiving this therapy. Geographic variation in the use of opioids has been demonstrated in the past, but there are no studies examining variation of chronic opioid use.
This study examines both the extent of geographic variation and the factors associated with variation across states of chronic opioid use among patients with FM.
Using a large, nationally representative dataset of commercially insured individuals, the following characteristics were examined: sex, disease prevalence, physician prevalence, illicit drug use, and the prescence of a prescription monitoring program. Other contextual and structural characteristics were also assessed.
The analysis included 245,758 patients with FM; 11.3% received chronic opioid therapy during the study period. There was a 5-fold difference between the states with the lowest rate of use (∼4%) and those with the highest (∼20%). The weighted %CV was 36.2%. Percent female and previous illicit opioid use rates were associated with higher rates of chronic opioid use, and FM prevalence and physician prevalence were associated with lower rates. The presence of a prescription monitoring program was not significantly correlated.
Geographic variation in chronic opioid use among patients with FM exists at rates similar to those seen in other studies examining opioid use. This large level of geographic variation suggests that the prescribing decision is not based solely on physician-patient interaction but also on contextual and structural factors at the state level. The level of physician and condition prevalence suggest that information dissemination and peer-to-peer interaction may play a key role in adopting evidence-based medicine for the treatment of patients suffering from FM and related conditions. Level of diagnosis prevalence as a predictor of evidence-based practice has not been reported in the literature and is an important contribution to research on geographic variation.
PMCID: PMC4346177  PMID: 23485077
chronic nonmalignant pain; fibromyalgia; FM; geographic variation; opioid
8.  Prostaglandin E2 activates RAP1 via EP2/EP4 receptors and cAMP-signaling in rheumatoid synovial fibroblasts: Involvement of EPAC1 and PKA 
The small GTPase Rap1 is implicated in a variety of cellar functions. In this study, we investigated the effect of prostaglandin E2 (PGE2) on Rap1 activation in rheumatoid synovial fibroblasts (RSF). Rap1 was expressed in RSF, and GTP-bound active Rap1 (GTP-Rap1) was rapidly increased by PGE2. The effect of PGE2 was mimicked by an EP2 receptor agonist, an EP4 agonist and a cAMP elevating agent forskolin with association to increase of cAMP, but not by an EP1 or an EP3 agonist. RSF expressed the downstream signaling partners of cAMP, exchange protein directly activated by cAMP (Epac1) and protein kinase A (PKA). Both 8-pCPT-2-O-Me-cAMP (an Epac-specific cAMP analog) and 6-Bnz-cAMP (a PKA-specific cAMP analog) activated Rap1 in RSF. Activation of Rap1 by PGE2 via cAMP signaling may play an important role in the articular pathology of rheumatoid arthritis (RA).
PMCID: PMC2738595  PMID: 19464664
9.  Modeling Bivariate Longitudinal Hormone Profiles by Hierarchical State Space Models 
The hypothalamic-pituitary-adrenal (HPA) axis is crucial in coping with stress and maintaining homeostasis. Hormones produced by the HPA axis exhibit both complex univariate longitudinal profiles and complex relationships among different hormones. Consequently, modeling these multivariate longitudinal hormone profiles is a challenging task. In this paper, we propose a bivariate hierarchical state space model, in which each hormone profile is modeled by a hierarchical state space model, with both population-average and subject-specific components. The bivariate model is constructed by concatenating the univariate models based on the hypothesized relationship. Because of the flexible framework of state space form, the resultant models not only can handle complex individual profiles, but also can incorporate complex relationships between two hormones, including both concurrent and feedback relationship. Estimation and inference are based on marginal likelihood and posterior means and variances. Computationally efficient Kalman filtering and smoothing algorithms are used for implementation. Application of the proposed method to a study of chronic fatigue syndrome and fibromyalgia reveals that the relationships between adrenocorticotropic hormone and cortisol in the patient group are weaker than in healthy controls.
PMCID: PMC3979568  PMID: 24729646
Circadian rhythm; Feedback Relationship; HPA axis; Kalman filter; Periodic splines
10.  Defective Generation of a Humoral Immune Response Is Associated with a Reduced Incidence and Severity of Collagen-Induced Arthritis in Microsomal Prostaglandin E Synthase-1 Null Mice1 
Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase and specifically catalyzes the conversion of PGH2 to PGE2. The present study demonstrates the effect of genetic deletion of mPGES-1 on the developing immunologic responses and its impact on the clinical model of bovine collagen-induced arthritis. mPGES-1 null and heterozygous mice exhibited decreased incidence and severity of arthritis compared with wild-type mice in a gene dose-dependent manner. Histopathological examination revealed significant reduction in lining hyperplasia and tissue destruction in mPGES-1 null mice compared with their wild-type littermates. mPGES-1 deficient mice also exhibited attenuation of mechanical nociception in a gene dose-dependent manner. In addition, mPGES-1 null and heterozygous mice showed a marked reduction of serum IgG against type II collagen (CII), including subclasses IgG1, IgG2a, IgG2b, IgG2c, and IgG3, compared with wild-type mice, which correlated with the reduction in observed inflammatory features. These results demonstrate for the first time that deficiency of mPGES-1 inhibits the development of collagen-induced arthritis, at least in part, by blocking the development of a humoral immune response against type II collagen. Pharmacologic inhibition of mPGES-1 may therefore impact both the inflammation and the autoimmunity associated with human diseases such as rheumatoid arthritis.
PMCID: PMC2435291  PMID: 18523303
11.  Sequential induction of pro- and anti-inflammatory prostaglandins and peroxisome proliferators activated receptor-gamma during normal wound healing: A time course study. 
Lipid mediators generated from metabolism of arachidonic acid play a crucial role in the initiating and resolution of acute inflammation by shifting from pro-inflammatory prostaglandin (PG) E2 to anti-inflammatory PGD2 and its metabolites. The changes in PG levels over time during the normal wound repair process have not, however, been reported. We determined the temporal expression of PG and their biosynthetic enzymes using the full thickness incisional model of normal wound healing in mice. We demonstrate that during normal wound repair, there is a shift in the metabolism of arachidonate from PGE2 during the acute inflammatory phase to PGD2 during the repair phase. This shift is mediated by temporal changes in the expression of cyclooxygenases (COX) and microsomal PGES (mPGES)-1. Inducible COX (COX-2) expression is sustained throughout the initiation and repair process, but mPGES-1 is increased only during the acute inflammatory phase and its disappearance coincides with increased PGD2. PGD2 and its degradation products are known to mediate their anti-inflammatory effects by binding to peroxisome proliferators activated receptor gamma (PPARγ). In this study, we show that PPARγ is upregulated during the resolution phase of wound repair concomitant with the shift to PGD2, and may be responsible for initiating endogenous mechanism resulting in healing/resolution.
PMCID: PMC1847382  PMID: 17239574
12.  Intrauterine Group A Streptococcal Infections are Exacerbated by Prostaglandin E2 
Streptococcus pyogenes(Group A Streptococcus; GAS) is a major cause of severe postpartum sepsis, a reemerging cause of maternal morbidity and mortality worldwide. Immunological alterations occur during pregnancy to promote maternofetal tolerance, which may increase the risk for puerperal infection. Prostaglandin E2 (PGE2) is an immunomodulatory lipid that regulates maternofetal tolerance, parturition, and innate immunity. The extent to which PGE2 regulates host immune responses to GAS infections in the context of endometritis is unknown. To address this, both an in vivo mouse intrauterine (i.u.) GAS infection model and an in vitro human macrophage-GAS interaction model were utilized. In C57BL/6 mice, i.u. GAS inoculation resulted in local and systemic inflammatory responses and triggered extensive changes in the expression of eicosanoid pathway genes. The i.u. administration of PGE2 increased the mortality of infected mice, suppressed local IL-6 and IL-17A levels, enhanced neutrophilic inflammation, reduced uterine macrophage populations, and increased bacterial dissemination. A role for endogenous PGE2 in modulating anti-streptococcal host defense was suggested because mice lacking the genes encoding the microsomal PGE2 synthase-1 or the EP2 receptor were protected from death, as were mice treated with the EP4 receptor antagonist GW627368X. PGE2 also regulated GAS-macrophage interactions. In GAS-infected human THP-1 (macrophage-like) cells, PGE2 inhibited the production of MCP-1 and TNF-α while augmenting IL-10 expression. PGE2 also impaired the phagocytic ability of human placental macrophages, THP-1 cells, and mouse peritoneal macrophages in vitro. Exploring the targeted disruption of PGE2 synthesis and signaling to optimize existing antimicrobial therapies against GAS may be warranted.
PMCID: PMC3750066  PMID: 23913961
13.  Diclofenac enables unprecedented week-long microneedle-enhanced delivery of a skin impermeable medication in humans 
Pharmaceutical research  2013;30(8):1947-1955.
Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals.
the purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans.
Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application.
Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n = 6), vs. 72 hours in Group 2 (placebo + naltrexone, n = 2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores).
This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases.
PMCID: PMC3773937  PMID: 23761054
microneedle; naltrexone; transdermal; diclofenac
14.  Development of in vivo impedance spectroscopy techniques for measurement of micropore formation following microneedle insertion 
Journal of pharmaceutical sciences  2013;102(6):1948-1956.
Microneedles provide a minimally invasive means to enhance skin permeability by creating micron-scale channels (micropores) that provide a drug delivery pathway. Adequate formation of the micropores is critical to the success of this unique drug delivery technique. The objective of these studies was to develop sensitive and reproducible impedance spectroscopy techniques to monitor micropore formation in animal models and human subjects. Hairless guinea pigs, a Yucatan miniature pig, and human volunteers were treated with 100 microneedle insertions per site following an overnight pre-hydration period. Repeated measurements were made pre- and post-microneedle treatment using dry and gel Ag/AgCl electrodes applied with light vs. direct pressure to hold the electrode to the skin surface. Impedance measurements dropped significantly post-microneedle application at all sites (p < 0.05, irrespective of electrode type or gel application), confirming micropore formation. In the Yucatan pig and human subjects, gel electrodes with direct pressure yielded the lowest variability (demonstrated by lower %RSD), whereas dry electrodes with direct pressure were superior in the guinea pigs. These studies confirm that impedance measurements are suitable for use in both clinical and animal research environments to monitor formation of new micropores that will allow for drug delivery through the impermeable skin layers.
PMCID: PMC3678392  PMID: 23589356
microneedle; impedance spectroscopy; micropore; transdermal; human
15.  Individual differences and self-regulatory fatigue: optimism, conscientiousness, and self-consciousness 
Personality and individual differences  2011;50(4):10.1016/j.paid.2010.11.011.
Ability to self-regulate varies and self-regulatory strength is a limited source that can be depleted or fatigued. Research on the impact of individual differences on self-regulatory capacity is still scarce, and this study aimed to examine whether personality factors such as dispositional optimism, conscientiousness, and self-consciousness can impact or buffer self-regulatory fatigue. Participants were patients diagnosed with chronic multi-symptom illnesses (N = 50), or pain free matched controls (N = 50), randomly assigned to either a high or low self-regulation task, followed by a persistence task. Higher optimism predicted longer persistence (p = .04), and there was a trend towards the same effect for conscientiousness (p = .08). The optimism by self-regulation interaction was significant (p = .01), but rather than persisting despite self-regulatory effort, optimists persisted longer only when not experiencing self-regulatory fatigue. The effects of optimism were stronger for controls than patients. There was also a trend towards a similar conscientiousness by self-regulation interaction (p = .06). These results suggest that the well-established positive impact of optimism and conscientiousness on engagement and persistence may be diminished or reversed in the presence of self-regulatory effort or fatigue, adding an important new chapter to the self-regulation, personality, and pain literature.
PMCID: PMC3882511  PMID: 24409005
Self-regulation; Self-regulatory fatigue; Dispositional optimism; Conscientiousness; Selfconsciousness
16.  The Association of Chronic Back Pain and Stress Urinary Incontinence: A Cross-Sectional Study 
The objective of this study was to investigate the association between chronic back pain and urinary incontinence in women.
Study Design
This study was a cross-sectional, observational study.
There are numerous factors associated with the development of back pain, yet little consideration has been given to the pelvic floor musculature and dysfunction of this musculature which may also cause urinary incontinence. Currently, limited research exists evaluating the relationship between back pain and urinary incontinence.
Methods and Measures
Data from a sample of 2,341 women from the Kentucky Women’s Health Registry were used for analysis. The primary variables of interest were self-reported chronic back pain (CBP) and stress urinary incontinence (SUI), with stress urinary incontinence serving as the primary dependent variable. Simple comparisons were performed using chi-square tests and two-sample t-tests, and multivariable associations were assessed using binary logistic regression.
Reports of stress urinary incontinence were higher in women reporting CBP than those not reporting CBP (49.0% vs. 35.2%, p<0.01). After controlling for potential confounders, the adjusted SUI odds ratio for CBP versus not was 1.44 (95% CI 1.11, 1.86).
Women who report CBP have an increased odds of having SUI. Therefore, clinicians must consider this association and the relationship of relevant trunk muscles, including pelvic floor musculature, in patients presenting with CBP and/or UI.
PMCID: PMC3688274  PMID: 23794961
17.  Diclofenac delays micropore closure following microneedle treatment in human subjects 
Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance–time curve (AUC) was calculated. AUC was significantly higher at MN + diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions.
PMCID: PMC3725617  PMID: 22929967
Microneedle; Transdermal; Diclofenac; Micropore; Human; Clinical
18.  Prostaglandin E2 Induction during Mouse Adenovirus Type 1 Respiratory Infection Regulates Inflammatory Mediator Generation but Does Not Affect Viral Pathogenesis 
PLoS ONE  2013;8(10):e77628.
Respiratory viruses cause substantial disease and are a significant healthcare burden. Virus-induced inflammation can be detrimental to the host, causing symptoms during acute infection and leading to damage that contributes to long-term residual lung disease. Prostaglandin E2 (PGE2) is a lipid mediator that is increased in response to many viral infections, and inhibition of PGE2 production during respiratory viral infection often leads to a decreased inflammatory response. We tested the hypothesis that PGE2 promotes inflammatory responses to mouse adenovirus type 1 (MAV-1) respiratory infection. Acute MAV-1 infection increased COX-2 expression and PGE2 production in wild type mice. Deficiency of the E prostanoid 2 receptor had no apparent effect on MAV-1 pathogenesis. Virus-induced induction of PGE2, IFN-γ, CXCL1, and CCL5 was reduced in mice deficient in microsomal PGE synthase-1 (mPGES-1-/- mice). However, there were no differences between mPGES-1+/+ and mPGES-1-/- mice in viral replication, recruitment of leukocytes to airways or lung inflammation. Infection of both mPGES‑1+/+ and mPGES-1-/- mice led to protection against reinfection. Thus, while PGE2 promotes the expression of a variety of cytokines in response to acute MAV-1 infection, PGE2 synthesis does not appear to be essential for generating pulmonary immunity.
PMCID: PMC3797793  PMID: 24147040
19.  Linking disease symptoms and subtypes with personalized systems-based phenotypes: A proof of concept study 
Brain, behavior, and immunity  2012;26(7):1047-1056.
A dynamic systems model was used to generate parameters describing a phenotype of Hypothalamic–Pituitary–Adrenal (HPA) behavior in a sample of 36 patients with chronic fatigue syndrome (CFS) and/ or fibromyalgia (FM) and 36 case-matched healthy controls. Altered neuroendocrine function, particularly in relation to somatic symptoms and poor sleep quality, may contribute to the pathophysiology of these disorders. Blood plasma was assayed for cortisol and ACTH every 10 min for 24 h. The dynamic model was specified with an ordinary differential equation using three parameters: (1) ACTH-adrenal signaling, (2) inhibitory feedback, and (3) non-ACTH influences. The model was ‘‘personalized’’ by estimating an individualized set of parameters from each participant’s data. Day and nighttime parameters were assessed separately. Two nocturnal parameters (ACTH-adrenal signaling and inhibitory feedback) significantly differentiated the two patient subgroups (“fatigue-predominant” patients with CFS only versus ‘‘pain-predominant’’ patients with FM and comorbid chronic fatigue) from controls (allp’s < .05), whereas daytime parameters and diurnal/nocturnal slopes did not. The same nocturnal parameters were significantly associated with somatic symptoms among patients (p’s < .05). There was a significantly different pattern of association between nocturnal non-ACTH influences and sleep quality among patients versus controls (p < .05). Although speculative, the finding that patient somatic symptoms decreased when more cortisol was produced per unit ACTH, is consistent with cortisol’s anti-inflammatory and sleep-modulatory effects. Patients’ HPA systems may compensate by promoting more rapid or sustained cortisol production. Mapping “behavioral phenotypes” of stress–arousal systems onto symptom clusters may help disentangle the pathophysiology of complex disorders with frequent comorbidity.
PMCID: PMC3725324  PMID: 22687333
Psychoneuroendocrinology; Stress–arousal; Cortisol; Glucocorticoid resistance; Feedback sensitivity; Dynamical systems; Systems medicine; Personalized medicine; Sleep quality; Somatic symptoms; Functional somatic disorders; Fibromyalgia; Chronic fatigue syndrome
20.  Gastric Antral Vascular Ectasia and Its Clinical Correlates in Patients with Early Diffuse Systemic Sclerosis in the SCOT Trial 
The Journal of rheumatology  2013;40(4):455-460.
To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; “watermelon stomach”) in early diffuse systemic sclerosis (SSc).
Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests.
Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003).
Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.
PMCID: PMC3652008  PMID: 23418384
21.  Development of Responder Definitions for Fibromyalgia Clinical Trials 
Arthritis and Rheumatism  2012;64(3):885-894.
To develop responder definitions for fibromyalgia clinical trials using key symptom and functional domains.
24 candidate responder definitions were developed by expert consensus and evaluated in 12 randomized, placebo-controlled fibromyalgia trials of 4 medications. For each definition, treatment effects of the medication compared with placebo were analyzed using the Cochran-Mantel-Haenszel test or Chi Square test. A meta-analysis of the pooled results for the 4 medications established risk ratios to determine the definitions that best favored medication over placebo.
Two definitions performed best in the analyses. Both definitions included ≥ 30% reduction in pain and ≥ 10% improvement in physical function. They differed in that one (FM30 short version) included ≥ 30% improvement in sleep or fatigue, and the other (FM30 long version) required ≥ 30% improvement in 2 of the following symptoms: sleep, fatigue, depression, anxiety, or cognition. In the analysis of both versions, the response rate was ≥ 15% for each medication and significantly greater than placebo. The risk ratio favoring drug over placebo (95% CI) in the pooled analysis for the FM30 short version was 1.50 (1.24, 1.82), P ≤ 0.0001; the FM30 long version was 1.60 (1.31, 1.96), P ≤ 0.00001.
Among the 24 responder definitions tested, 2 were identified as most sensitive in identifying response to treatment. The identification of responder definitions for fibromyalgia clinical trials that include assessments of key symptom and functional domains may improve the sensitivity of clinical trials to identify meaningful improvements, leading to improved management of fibromyalgia.
PMCID: PMC3252491  PMID: 21953205
22.  Noninvasive optical characterization of muscle blood flow, oxygenation, and metabolism in women with fibromyalgia 
Arthritis Research & Therapy  2012;14(6):R236.
Women with fibromyalgia (FM) have symptoms of increased muscular fatigue and reduced exercise tolerance, which may be associated with alterations in muscle microcirculation and oxygen metabolism. This study used near-infrared diffuse optical spectroscopies to noninvasively evaluate muscle blood flow, blood oxygenation and oxygen metabolism during leg fatiguing exercise and during arm arterial cuff occlusion in post-menopausal women with and without FM.
Fourteen women with FM and twenty-three well-matched healthy controls participated in this study. For the fatiguing exercise protocol, the subject was instructed to perform 6 sets of 12 isometric contractions of knee extensor muscles with intensity steadily increasing from 20 to 70% maximal voluntary isometric contraction (MVIC). For the cuff occlusion protocol, forearm arterial blood flow was occluded via a tourniquet on the upper arm for 3 minutes. Leg or arm muscle hemodynamics, including relative blood flow (rBF), oxy- and deoxy-hemoglobin concentration ([HbO2] and [Hb]), total hemoglobin concentration (THC) and blood oxygen saturation (StO2), were continuously monitored throughout protocols using a custom-built hybrid diffuse optical instrument that combined a commercial near-infrared oximeter for tissue oxygenation measurements and a custom-designed diffuse correlation spectroscopy (DCS) flowmeter for tissue blood flow measurements. Relative oxygen extraction fraction (rOEF) and oxygen consumption rate (rVO2) were calculated from the measured blood flow and oxygenation data. Post-manipulation (fatiguing exercise or cuff occlusion) recovery in muscle hemodynamics was characterized by the recovery half-time, a time interval from the end of manipulation to the time that tissue hemodynamics reached a half-maximal value.
Subjects with FM had similar hemodynamic and metabolic response/recovery patterns as healthy controls during exercise and during arterial occlusion. However, tissue rOEF during exercise in subjects with FM was significantly lower than in healthy controls, and the half-times of oxygenation recovery (Δ[HbO2] and Δ[Hb]) were significantly longer following fatiguing exercise and cuff occlusion.
Our results suggest an alteration of muscle oxygen utilization in the FM population. This study demonstrates the potential of using combined diffuse optical spectroscopies (i.e., NIRS/DCS) to comprehensively evaluate tissue oxygen and flow kinetics in skeletal muscle.
PMCID: PMC3674608  PMID: 23116302
23.  Potential roles of microsomal prostaglandin E synthase-1 in rheumatoid arthritis 
Inflammation and regeneration  2011;31(2):157-166.
Rheumatoid arthritis (RA) is a chronic autoimmune disease which primarily affects the synovial joints leading to inflammation, pain and joint deformities. Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, both of which inhibit cyclooxygenase (COX), have been extensively used for treating RA patients. Prostaglandin E synthase (PGES) is a specific biosynthetic enzyme that acts downstream of COX and converts prostaglandin (PG) H2 to PGE2. Among PGES isozymes, microsomal PGES-1 (mPGES-1) has been shown to be induced in a variety of cells and tissues under inflammatory conditions. The induction of mPGES-1 in the synovial tissue of RA patients is closely associated with the activation of the tissue by proinflammatory cytokines. Although selective mPGES-1 inhibitors have not yet been widely available, mice lacking mPGES-1 (mPGES-1–/– mice) have been generated to evaluate the physiological and pathological roles of mPGES-1 in vivo. Recent studies utilizing mPGES-1–/– mice have demonstrated the significance of mPGES-1 in the process of chronic inflammation and evocation of humoral immune response in autoimmune arthritis models. These recent findings highlight mPGES-1 as a novel therapeutic target for the treatment of autoimmune inflammatory diseases, including RA. Currently, both natural and synthetic chemicals are being tested for inhibition of mPGES-1 activity to produce PGE2. The present review focuses on the recent advances in understanding the role of mPGES-1 in the pathophysiology of RA.
PMCID: PMC3269760  PMID: 22308189
inflammation; microsomal prostaglandin E synthase-1; prostaglandin E2; rheumatoid arthritis; T-cell-dependent humoral immunity
24.  Predictors of survival in a cohort of patients with polymyositis and dermatomyositis: effect of corticosteroids, methotrexate and azathioprine 
The idiopathic inflammatory myopathies are rare diseases for which data regarding the natural history, response to therapies and factors affecting mortality are needed. We performed this study to examine the effects of treatment and clinical features on survival in polymyositis and dermatomyositis patients.
A total of 160 consecutive patients (77 with polymyositis and 83 with dermatomyositis) seen at the University of Michigan from 1997 to 2003 were included. Medical records were abstracted for clinical, laboratory and therapeutic data, including initial steroid regimen and immunosuppressive use. State vital records were utilized to derive mortality and cause of death data. Survival was modeled by left-truncated Kaplan-Meier estimation and Cox regression.
The 5- and 10-year survival estimates were 77% (95% CI = 66 to 85), and 62% (95% CI = 48 to 73), respectively, and the rates were similar for polymyositis and dermatomyositis. Survival between the sexes was similar through 5 years and significantly lower thereafter for males (10-year survival: 18% male, 73% female; P = 0.002 for 5- to 10-year interval). The sex disparity was restricted to the polymyositis group. Increased age at diagnosis and non-Caucasian race were associated with lower survival. Intravenous versus oral corticosteroid use was associated with a higher risk of death among Caucasians (HR = 10.6, 95% CI = 2.1 to 52.8). Early survival between patients treated with methotrexate versus azathioprine was similar, but survival at 10 years was higher for the methotrexate-treated group (76% vs 52%, P = 0.046 for 5- to 10-year interval).
Patients treated initially with intravenous corticosteroids had higher mortality, which was likely related to disease severity. Both methotrexate and azathioprine showed similar early survival benefits as first-line immunosuppressive drugs. Survival was higher between 5 and 10 years in the methotrexate-treated group, but could not be confirmed in multivariable modeling for the full follow-up period. Other important predictors of long-term survival included younger age, female sex and Caucasian race.
PMCID: PMC3392815  PMID: 22284862
25.  Rheumatoid Arthritis and Salivary Biomarkers of Periodontal Disease 
Journal of clinical periodontology  2010;37(12):1068-1074.
To test the hypothesis that rheumatoid arthritis influenced levels of salivary biomarkers of periodontal disease.
Medical assessments, periodontal examinations, and pain ratings were obtained from 35 rheumatoid arthritis, 35 chronic periodontitis and 35 age and gender-matched healthy controls in a cross-sectional, case-controlled study. Unstimulated whole saliva samples were analyzed for interleukin-1β (IL-1β), matrix-metalloproteinase-8 (MMP-8) and tumor necrosis factor-α (TNF)-α concentrations.
The arthritis and healthy groups had significantly less oral disease than the periodontitis group (p<0.0001), with the arthritis group having significantly more sites bleeding on probing (BOP) than matched controls (p=0.012). Salivary levels of MMP-8 and IL-1β were significantly elevated in the periodontal disease group (p≤0.002), and IL-1β was the only biomarker with significantly higher levels in the arthritis group compared with controls (p=0.002). Arthritis patients receiving anti-TNF-α antibody therapy had significantly lower IL-1β and TNF-α levels compared with arthritis patients not on anti-TNF-α therapy (p=0.016, p=0.024) and healthy controls (p<0.001, p=0.011), respectively.
Rheumatoid arthritis patients have higher levels of periodontal inflammation than healthy controls, ie. increased BOP. Systemic inflammation appears to influence levels of select salivary biomarkers of periodontal disease, and anti-TNF-α antibody-based disease modifying therapy significantly lowers salivary IL-1β and TNF-α levels in rheumatoid arthritis.
PMCID: PMC2980566  PMID: 20880053
Interleukin 1β; matrix metalloproteinase (MMP); tumor necrosis factor (TNF)-α; salivary biomarkers; periodontal disease; rheumatoid arthritis; saliva; inflammation; biological markers

Results 1-25 (36)