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Biomedical subjects

Leslie J Crofford

Publications and source records attributed to Leslie J Crofford.

At least 19 recordsLinked to original sources
PubMed2006

Microsomal prostaglandin E synthase-1 deficiency is associated with elevated peroxisome proliferator-activated receptor gamma: regulation by prostaglandin E2 via the phosphatidylinositol 3-kinase and Akt pathway.

mPGES-1 (microsomal PGE synthase-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin (PG) H(2) to PGE(2) under basal as well as inflammatory conditions. In this study, using mouse embryo fibroblasts (MEFs) isolated from mice genetically deficient for the mPges-1 gene, we show basal elevation of peroxisome proliferator-activated receptor gamma (PPARgamma) expression (protein and mRNA) and transcriptional activity associated with reduced basal PGE(2). We further show that basal mPGES-1-derived PGE(2) suppresses the expression of PPARgamma through a cAMP-independent pathway involving phosphatidylinositol 3-kinase and Akt signaling. Using specific PPARgamma agonist (rosiglitazone), PPARgamma ligand (15-deoxy-Delta12,14-PGJ(2)), and PPARgamma inhibitor (GW9662), we confirm that activation of PPARgamma blocks interleukin-1beta-induced up-regulation of COX-2, mPGES-1, and their derived PGE(2). Furthermore, we demonstrate that up-regulation of PPARgamma upon genetic deletion of mPGES-1 is responsible for reduced COX-2 expression under basal as well as interleukin-1beta-stimulated conditions. This study provides evidence for the first time that mPGES-1 deletion not only decreases proinflammatory PGE(2) but also up-regulates anti-inflammatory PPARgamma, which has the ability to suppress COX-2 and mPGES-1 expression and PGE(2) production. Thus, mPGES-1 inhibition may limit inflammation by multiple mechanisms and is a potential therapeutic target.

Animals↗
PubMed2006

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 prostaglandin (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)-1beta, 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 PGF1alpha (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.

Animals↗
PubMed2006

Cardiovascular effects of selective COX-2 inhibition: is there a class effect? The International COX-2 Study Group.

The International COX-2 Study Group, a panel of independent physicians and scientists, convened January 28-30, 2005, in Washington, DC, to discuss the issues concerning the cardiovascular (CV) profile of coxibs. The purpose of the meeting was to review potential mechanisms by which inhibition of COX-2 by selective and nonselective NSAID could increase risk of CV events, to evaluate the similarities and differences between drugs based on mechanism and pharmacology, and to propose potential trial methodology to more definitively answer questions regarding cardiovascular risk.

Arthritis, Rheumatoid↗
PubMed2006

Major enzymatic pathways in dermal wound healing: current understanding and future therapeutic targets.

Skin is an essential protective organ for vertebrate animals. During skin injury, a plethora of cells and mediators occupy the wound site and, through a collective effort, perform repair of the tissue. This complex pathophysiological process is referred to as wound healing. The efficiency of wound repair is governed by the sequential influx of a variety of cell types to the wound site, upregulation/downregulation of many signaling molecules, and the interaction of various enzymatic pathways. Any dysregulation in this highly complex, but orderly, pathophysiological process results in impaired wound repair. A variety of metabolic enzymes are induced upon injury and are responsible for driving the key physiological processes within the wound milieu during the inflammatory and resolution phases of wound repair. This review will focus on the contribution of major enzymatic biosystems to the inflammatory, remodeling and resolution phases of normal wound healing, including the arachidonic acid metabolic pathway, L-arginine metabolism and the endogenous oxidant-antioxidant redox systems of the body. The major therapeutic targets within these processes will also be highlighted.

Animals↗
PubMed2005

Microsomal prostaglandin E synthase-1: the inducible synthase for prostaglandin E2.

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme that catalyzes the conversion of prostaglandin (PG)H2 to PGE2. Proinflammatory stimuli markedly increase levels of mPGES-1 expression both in vivo and in vitro. mPGES-1 knockout studies and animal models of inflammatory arthritis also provide a strong basis for the contribution of mPGES-1 in the increased local production of PGE2 observed in inflammatory arthritis. The focus of this article is to review some recent advances in our understanding of mechanisms specific to the regulation of inducible mPGES-1 in inflammatory arthritis.

Animals↗
PubMed2005

Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Fibromyalgia syndrome (FMS) is characterized by widespread musculoskeletal pain and lowered pain threshold. Other prominent symptoms include disordered sleep and fatigue. FMS affects an estimated 2% of the population, predominantly women. This trial was designed to evaluate the efficacy and safety of pregabalin, a novel alpha(2)-delta ligand, for treatment of symptoms associated with FMS. METHODS: This multicenter, double-blind, 8-week, randomized clinical trial compared the effects of placebo with those of 150, 300, and 450 mg/day pregabalin on pain, sleep, fatigue, and health-related quality of life in 529 patients with FMS. The primary outcome variable was the comparison of end point mean pain scores, derived from daily diary ratings of pain intensity, between each of the pregabalin treatment groups and the placebo group. RESULTS: Pregabalin at 450 mg/day significantly reduced the average severity of pain in the primary analysis compared with placebo (-0.93 on a 0-10 scale) (P </= 0.001), and significantly more patients in this group had >/=50% improvement in pain at the end point (29%, versus 13% in the placebo group; P = 0.003). Pregabalin at 300 and 450 mg/day was associated with significant improvements in sleep quality, fatigue, and global measures of change. Pregabalin at 450 mg/day improved several domains of health-related quality of life. Dizziness and somnolence were the most frequent adverse events. Rates of discontinuation due to adverse events were similar across all 4 treatment groups. CONCLUSION: Pregabalin at 450 mg/day was efficacious for the treatment of FMS, reducing symptoms of pain, disturbed sleep, and fatigue compared with placebo. Pregabalin was well tolerated and improved global measures and health-related quality of life.

Adult↗
PubMed2005

Momentary relationship between cortisol secretion and symptoms in patients with fibromyalgia.

OBJECTIVE: To compare the momentary association between salivary cortisol levels and pain, fatigue, and stress symptoms in patients with fibromyalgia (FM), and to compare diurnal cycles of cortisol secretion in patients with FM and healthy control subjects in a naturalistic environment. METHODS: Twenty-eight patients with FM and 27 healthy control subjects completed assessments on salivary cortisol levels and pain, fatigue, and stress symptoms, 5 times a day for 2 consecutive days, while engaging in usual daily activities. Only those participants who adhered to the protocol (assessed via activity monitor) were included in the final analyses. RESULTS: Twenty FM patients and 16 healthy control subjects adhered to the protocol. There were no significant differences in cortisol levels or diurnal cortisol variation between FM patients and healthy controls. Among women with FM, a strong relationship between cortisol level and current pain symptoms was observed at the waking time point (t = 3.35, P = 0.008) and 1 hour after waking (t = 2.97, P = 0.011), but not at the later 3 time points. This association was not due to differences in age, number of symptoms of depression, or self-reported history of physical or sexual abuse. Cortisol levels alone explained 38% and 14% of the variation in pain at the waking and 1 hour time points, respectively. No relationship was observed between cortisol level and fatigue or stress symptoms at any of the 5 time points. CONCLUSION: Among women with FM, pain symptoms early in the day are associated with variations in function of the hypothalamic-pituitary-adrenal axis.

Adult↗
PubMed2005

Adenovirus binding to cultured synoviocytes triggers signaling through MAPK pathways and induces expression of cyclooxygenase-2.

BACKGROUND: Recombinant adenovirus can be administered in vivo to achieve transduction of a number of cell types including human synoviocytes. Immunogenicity of adenoviruses has limited their utility as vectors for gene delivery; however, specific mechanisms underlying the acute inflammatory response to adenovirus are not well understood. Activation of a number of signal transduction pathways occurs rapidly upon adenovirus binding to cell-surface receptors. We investigated stimulated expression of mitogen-activated protein kinases (MAPKs), cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) in human primary synovial fibroblasts to adenovirus expressing the E. coli beta-galactosidase gene. METHODS: Cultured rheumatoid synoviocytes were exposed to transduction-competent Ad/RSVlacZ recombinant adenovirus or transduction-incompetent (psoralen/UV-irradiated) Ad/RSVlacZ. The effects on COX-2 expression, PGE(2) levels and MAPK signaling in synoviocytes were assessed using a combination of reverse-transcription polymerase chain reaction amplification and immunoblotting. RESULTS: Adenovirus treatment of synoviocytes increased levels of COX-2 mRNA and protein as well as PGE(2). Psoralen-treated transcriptionally inactive adenovirus was equivalent to untreated adenovirus for early COX-2 induction suggesting that viral genes were not required. Adenovirus treatment stimulated phosphorylation of ERK-1/-2, p38 MAPK, and JNK. Inhibition of the ERK and p38 MAPK pathways inhibited COX-2 expression and PGE(2) production. CONCLUSIONS: Taken together, these data demonstrate that a MAPK-dependent increase in COX-2 results in local prostaglandin production. These findings have clinical implications for use of adenovirus as vectors for in vivo gene delivery.

Adenoviridae↗
PubMed2005

Immunomodulatory therapy for SSc: will high-intensity immunosuppression with stem cell rescue improve outcome?

Effective treatments for severe systemic sclerosis (SSc) have not been identified. SSc is associated with high levels of morbidity and mortality related to functional impairment and organ dysfunction. The pathogenesis of SSc, as with all autoimmune disorders, is thought to involve the interplay between genetic background and environmental exposures. Abundant evidence exists for activation of humoral and cellular immunity in SSc. These immune and inflammatory mechanisms almost certainly play a role in vascular damage and activation of pathways that lead to fibrosis. However, the types and intensities of immunomodulatory therapies employed in other connective tissue diseases have not proved as useful in patients with SSc. The question remains if increasing the intensity of immunosuppression will prove a more successful strategy. Preliminary studies of intensification of therapy to immunoablative and myeloablative levels with hematopoietic stem cell rescue have been performed and appear promising. New studies to compare these approaches with conventional immunomodulatory therapy are underway.

Hematopoietic Stem Cell Transplantation↗
PubMed2005

Memory beliefs and function in fibromyalgia patients.

OBJECTIVE: The aim of this study was to investigate memory beliefs and their relationship to actual memory function in fibromyalgia (FM) patients. METHODS: Twenty-three FM patients, 23 age- and education-matched controls, and 22 older controls completed the Metamemory in Adulthood (MIA) questionnaire, which assessed beliefs about seven aspects of memory function. Group differences on the seven scales were assessed, and scores on the capacity scale were correlated with objective memory performance. RESULTS: FM patients reported lower memory capacity and more memory deterioration than did either control group. Patients reported lower control or self-efficacy over memory, higher achievement motivation, higher strategy use, and higher anxiety about memory than age-matched controls did. Among the patients, perceived capacity, achievement motivation, and self-efficacy were significantly correlated with objective memory performance on a recall task. CONCLUSION: FM patients' complaints about memory function have some accuracy.

Achievement↗
PubMed2005

The relationship of fibromyalgia to neuropathic pain syndromes.

The appropriateness and utility of considering fibromyalgia syndrome (FM) and other syndromes without anatomically localized pathology of the nervous system as neuropathic pain syndromes is uncertain. In this afterword, a synthesis of the information presented in these proceedings and opinion as to how FM relates to classical neuropathic pain syndromes is provided.

Animals↗
PubMed2005

Fibromyalgia syndrome.

The objectives of the first OMERACT Fibromyalgia Syndrome (FM) Workshop were to identify and prioritize symptom domains that should be consistently evaluated in FM clinical trials, and to identify aspects of domains and outcome measures that should be part of a concerted research agenda of FM researchers. Such an effort will help standardize and improve the quality of outcomes research in FM. A principal assumption in this workshop has been that there exists a clinical syndrome, generally known as FM, characterized by chronic widespread pain typically associated with fatigue, sleep disturbance, mood disturbance, and other symptoms and signs, and considered to be related to central neuromodulatory dysregulation. FM can be diagnosed using 1990 American College of Rheumatology criteria. In preparation for the workshop a Delphi exercise involving 23 FM researchers was conducted to establish a preliminary prioritization of domains of inquiry. At the OMERACT meeting, the workshop included presentation of the Delphi results; a review of placebo-controlled trials of FM treatment, with a focus on the outcome measures used and their performance; a panel discussion of the key issues in FM trials, from both an investigator and regulatory agency perspective; and a voting process by the workshop attendees. The results of the workshop were presented in the plenary session on the final day of the meeting. A prioritized list of domains of FM to be investigated was thus developed, key issues and controversies in the field were debated, and consensus on a research agenda on outcome measure development was reached.

Delphi Technique↗
PubMed2005

Growth factor receptors: implications in tumor biology.

Growth factors are signaling molecules which bind to cell surface receptors and mediate a myriad of intracellular functions. Growth factor signaling is vital for growth and differentiation of cells under normal physiological conditions. However, aberrant signaling of these molecules via their receptors enables the cells to acquire abnormal characteristics most commonly observed in tumor cells. Tumor biology studies have revealed a central role for growth factor receptors in tumor progression. This review discusses the involvement of growth factor receptors in solid tumor formation and their value as potential anticancer drug targets.

Animals↗
PubMed2004

A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder.

OBJECTIVE: To assess the efficacy and safety of duloxetine, a serotonin and norepinephrine reuptake inhibitor, in subjects with primary fibromyalgia, with or without current major depressive disorder. METHODS: This study was a randomized, double-blind, placebo-controlled trial conducted in 18 outpatient research centers in the US. A total of 207 subjects meeting the American College of Rheumatology criteria for primary fibromyalgia were enrolled (89% female, 87% white, mean age 49 years, 38% with current major depressive disorder). After single-blind placebo treatment for 1 week, subjects were randomly assigned to receive duloxetine 60 mg twice a day (n = 104) or placebo (n = 103) for 12 weeks. Co-primary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ) total score (score range 0-80, with 0 indicating no impact) and FIQ pain score (score range 0-10). Secondary outcome measures included mean tender point pain threshold, number of tender points, FIQ fatigue, tiredness on awakening, and stiffness scores, Clinical Global Impression of Severity (CGI-Severity) scale, Patient Global Impression of Improvement (PGI-Improvement) scale, Brief Pain Inventory (short form), Medical Outcomes Study Short Form 36, Quality of Life in Depression Scale, and Sheehan Disability Scale. RESULTS: Compared with placebo-treated subjects, duloxetine-treated subjects improved significantly more (P = 0.027) on the FIQ total score, with a treatment difference of -5.53 (95% confidence interval -10.43, -0.63), but not significantly more on the FIQ pain score (P = 0.130). Compared with placebo-treated subjects, duloxetine-treated subjects had significantly greater reductions in Brief Pain Inventory average pain severity score (P = 0.008), Brief Pain Inventory average interference from pain score (P = 0.004), number of tender points (P = 0.002), and FIQ stiffness score (P = 0.048), and had significantly greater improvement in mean tender point pain threshold (P = 0.002), CGI-Severity (P = 0.048), PGI-Improvement (P = 0.033), and several quality-of-life measures. Duloxetine treatment improved fibromyalgia symptoms and pain severity regardless of baseline status of major depressive disorder. Compared with placebo-treated female subjects (n = 92), duloxetine-treated female subjects (n = 92) demonstrated significantly greater improvement on most efficacy measures, while duloxetine-treated male subjects (n = 12) failed to improve significantly on any efficacy measure. The treatment effect on significant pain reduction in female subjects was independent of the effect on mood or anxiety. Duloxetine was safely administered and well tolerated. CONCLUSION: In this randomized, controlled, 12-week trial (with a 1-week placebo lead-in phase), duloxetine was an effective and safe treatment for many of the symptoms associated with fibromyalgia in subjects with or without major depressive disorder, particularly for women, who had significant improvement across most outcome measures.

Comorbidity↗
PubMed2004

Pharmaceutical treatment options for fibromyalgia.

Fibromyalgia syndrome (FMS) is a chronic multisymptom illness characterized by widespread pain and associated with neuropsychological symptoms including fatigue, unrefreshing sleep, cognitive dysfunction, anxiety, and depression. A discreet cause of FMS has not been identified. It is likely that multiple mechanisms give rise to symptom expression. Understanding specific etiologic factors and pathogenic mechanisms in individual patients will allow clinicians to determine treatments that are most effective for a given patient. Available evidence implicates the central nervous system as key in maintaining pain and other core symptoms of FMS. The approach to treatment of pain will typically address these central mechanisms. Nonpain symptoms may be treated by drugs affecting similar central neurochemicals. This paper will review the rationale for the different types of pharmaceutical treatments that may be useful for the treatment of FMS and issues regarding new drug development for this indication.

Analgesics↗
PubMed2004

Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome.

The objective of this study was to evaluate and compare the basal circadian and pulsatile architecture of the HPA axis in groups of patients with FMS, CFS, or both syndromes with individually matched control groups. Forty patients with either FMS (n = 13), FMS and CFS (n = 12), or CFS (n = 15) were matched by age (18-65), sex, and menstrual status to healthy controls. Subjects were excluded if they met criteria for major Axis I psychiatric disorders by structured clinical interview (SCID). Subjects were admitted to the General Clinical Research Center where meals and activities were standardized. Blood was collected from an intravenous line every 10 min over 24 h for analysis of ACTH and cortisol. Samples were evaluable for ACTH in 36 subject pairs and for cortisol in 37 subject pairs. There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P <.01). Elevation of cortisol in the late evening quiescent period was evident in half of the FMS patients compared with their control group, while cortisol levels were numerically, but not significantly, lower in the overnight period in patients with CFS compared with their control group. Pulsatility analyses did not reveal statistically significant differences between patient and control groups. We conclude that the pattern of differences for basal circadian architecture of HPA axis hormones differs between patients with FMS and CFS compared to their matched control groups. The abnormalities in FMS patients are consistent with loss of HPA axis resiliency.

Adrenocorticotropic Hormone↗
PubMed2003

Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure.

BACKGROUND: Nephrogenic fibrosing dermopathy is a newly recognized cutaneous fibrosing disorder marked by the acute onset of induration involving the upper and lower limbs in patients with acute or chronic renal failure. The etiology, pathogenesis, associated clinical conditions (other than renal failure), and ultimate course have not been defined in the few cases studied. Presently, there is no effective treatment, and the condition persists in most patients. METHODS: Clinical and histopathologic data on 13 patients from our institution with the diagnosis of nephrogenic fibrosing dermopathy were reviewed. Several clinical and laboratory parameters were examined to see if any were consistently associated with the disease. Biopsy specimens were analyzed to determine if there was a pattern to the evolution of fibrosis in these patients. RESULTS: All 13 patients had renal failure before disease onset: 8 were undergoing chronic hemodialysis, 2 were undergoing chronic peritoneal dialysis, and 3 with acute renal failure had never undergone dialysis before the development of dermopathy. Most patients had other serious underlying medical conditions. Many patients were taking erythropoietin, cyclosporine, or both before the onset of disease. In transplant patients, no histocompatibility antigens were found to be associated with the disease. There were various laboratory abnormalities, but none were consistently associated with the condition. In skin biopsy specimens taken 7 to 180 days after disease onset, there were histopathologic changes suggestive of a tissue reaction to injury, as well as the development of smooth muscle actin-positive myofibroblasts. CONCLUSION: Nephrogenic fibrosing dermopathy is a novel cutaneous fibrosing disorder that is distinguished from other sclerosing or fibrosing skin disorders by distinctive clinical and histopathologic findings occurring in the setting of renal failure. There were no additional clinical risk factors or laboratory findings common to the 13 patients studied, other than renal failure. The resemblance to a tissue injury reaction and the presence of myofibroblasts in the tissue specimens suggest that fibrogenic cytokines may be involved in the evolution of the disease.

Adult↗
PubMed2003

Perception of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: association with mood, somatic focus, and catastrophizing.

Recent studies have demonstrated that persons with fibromyalgia display abnormal processing of different types of painful stimulation, suggesting the disorder is characterized by a central pain-processing deficit not limited specifically to muscle pain. In the present study, 20 women with fibromyalgia and 20 normal, healthy women were compared on measures of pressure pain stimulation and response to contact thermal heat at both noxious and innocuous intensities. Women with fibromyalgia displayed significantly lower pressure pain thresholds at 18 tender point locations as defined by the American College of Rheumatology criteria, as well as lower pressure pain thresholds at five control sites. Women with fibromyalgia had significantly lower heat pain thresholds and tolerances when stimulated on the volar surface of the left forearm. When examining visual analog ratings of intensity and unpleasantness to constant stimuli, a multivariate analysis of variance performed on these ratings indicated that there were significant main effects of level of stimulation and group. Individual analysis of variances at each temperature revealed significant differences between the groups in pain intensity and unpleasantness ratings at both noxious and innocuous temperatures. Multiple regression analyses indicated that greater pain catastrophizing and diagnosis of fibromyalgia were associated with decreased pain thresholds and tolerances in the entire sample, whereas, self-report of depressive symptoms was associated with increased thresholds and tolerances. Self-report of somatic symptoms was not associated with these measures. These findings indicate that persons with fibromyalgia display altered perception of both pressure and thermal stimulation, even at innocuous levels. They also suggest that catastrophic thoughts about pain may play a role in increased pain perception in this population.

Adult↗