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Biomedical subjects

L J Crofford

Publications and source records attributed to L J Crofford.

At least 19 recordsLinked to original sources
PubMed2005

Comparison of disease progression and mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia.

OBJECTIVE: To compare disease progression and mortality between idiopathic interstitial pneumonia (IIP) and interstitial lung disease (ILD) due to connective tissue diseases (CTD) including scleroderma, rheumatoid arthritis, systemic lupus, polymyositis, dermatomyositis, Sjögren's syndrome, and mixed CTD. METHODS: A case-control study of patients with CTD-ILD (n = 46) and IIP controls (n = 51), seen at the University of Michigan between July 1,1998 and June 30,1999 and followed until March 30, 2002, was conducted. Survival analysis and Cox regression were performed to estimate survival, accounting for demographic and clinical parameters, including pulmonary function tests and high resolution computed tomography (HRCT) diagnosis and scoring. RESULTS: Median followup time was 4.4 person-years. Five-year survival in the IIP group was 51.9% (95% confidence interval [95% CI] 30.8-69.4) versus 43.4% (95% CI 21.1-63.9) in the CTD-ILD group. There were no significant differences among HRCT diagnostic categories between IIP and CTD-ILD. A fibrotic score > or = 2 was associated with decreased survival among the entire group. Age at diagnosis and most recent forced vital capacity were significant predictors of mortality when adjusted for IIP versus CTD-ILD diagnosis, sex, and interstitial score. CONCLUSION: Contrary to expectation, CTD-ILD compared with IIP appears to be associated with a worse prognosis when adjusted for age. A higher fibrotic score is suggestive of decreased survival.

Adult↗
PubMed2002

A 588-gene microarray analysis of the peripheral blood mononuclear cells of spondyloarthropathy patients.

OBJECTIVES: To identify genes which are more highly expressed in the peripheral blood mononuclear cells (PBMC) of patients with spondyloarthropathy (SpA), rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in comparison to normal subjects. METHODS: A 588-gene microarray was used as a screening tool to select a panel of such genes from PBMC of these subjects and of normal subjects. Results were then validated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The following genes were more highly expressed in arthritis patients than in normal subjects: macrophage differentiation marker MNDA (myeloid nuclear differentiation antigen), MRP8 and MRP14 (migratory inhibitory factor-related proteins); signalling molecules JAK3 (janus kinase 3) and MAP kinase p38 (mitogen-activated protein kinase); receptors TNFR2/p75, C-C-chemokine receptor type 1 (CCR1), C-X-C-chemokine receptor type 4 (CXCR4) and integrin beta1; and the cytokines/chemokines interleukin (IL) 1beta and IL-8. Expression of CXCR4 was unexpectedly high among all arthritis subjects. Using RT-PCR, ELISA and immunohistology, expression of stromal cell-derived factor 1 (SDF-1) was demonstrated in arthritis joints. CONCLUSIONS: The CXCR4/SDF-1 is a potential pro-inflammatory axis for RA, PsA and SpA.

Adolescent↗
PubMed2001

Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries.

BACKGROUND: Prostanoid synthesis via the action of cyclooxygenase-2 (COX-2) is a component of the inflammatory response. Prostacyclin, a product of COX-2 in vascular endothelium, has important physiological roles, such as increasing blood flow to injured tissues, reducing leukocyte adherence, and inhibiting platelet aggregation. We examined the possibility that selective COX-2 inhibition could suppress the protective effects of prostacyclin, resulting in an alteration of the hemostatic balance and vascular tone. METHODS AND RESULTS: Circumflex coronary artery thrombosis was induced in dogs by vascular electrolytic injury. Orally administered celecoxib (COX-2 inhibition) or high-dose aspirin (HDA) (COX-1 and COX-2 inhibition) did not alter time to occlusive thrombus formation compared with controls (celecoxib 77.7+/-7.2 minutes, HDA 72.0+/-18.5 minutes, control 93.0+/-21.8 minutes). Oral HDA with an endothelial recovery period (HDA-ER) (COX-1 inhibition) produced a significant increase in time to vessel occlusion (257.0+/-41.6 minutes). The observed increase in time to occlusion was abolished when celecoxib was administered to animals dosed with HDA-ER (80.7+/-20.6 minutes). The vasomotor effect of endothelium-derived prostacyclin was examined by monitoring coronary flow during intracoronary administration of arachidonic acid or acetylcholine. In celecoxib-treated animals, vasodilation in response to arachidonic acid was reduced significantly compared with controls. CONCLUSIONS: The results indicate important physiological roles for COX-2-derived prostacyclin and raise concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be increased in individuals with underlying inflammatory disorders, including coronary artery disease.

Acetylcholine↗
PubMed2001

Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells.

The selective induction of PGE(2) synthesis in inflammation suggests that a PGE synthase may be linked to an inducible pathway for PG synthesis. We examined the expression of the recently cloned inducible microsomal PGE synthase (mPGES) in synoviocytes from patients with rheumatoid arthritis, its modulation by cytokines and dexamethasone, and its linkage to the inducible cyclooxygenase-2. Northern blot analysis showed that IL-1beta or TNF-alpha treatment induces mPGES mRNA from very low levels at baseline to maximum levels at 24 h. IL-1beta-induced mPGES mRNA was inhibited by dexamethasone in a dose-dependent fashion. Western blot analysis demonstrated that mPGES protein was induced by IL-1beta, and maximum expression was sustained for up to 72 h. There was a coordinated up-regulation of cyclooxygenase-2 protein, although peak expression was earlier. Differential Western blot analysis of the microsomal and the cytosolic fractions revealed that the induced expression of mPGES protein was limited to the microsomal fraction. The detected mPGES protein was catalytically functional as indicated by a 3-fold increase of PGES activity in synoviocytes following treatment with IL-1beta; this increased synthase activity was limited to the microsomal fraction. In summary, these data demonstrate an induction of mPGES in rheumatoid synoviocytes by proinflammatory cytokines. This novel pathway may be a target for therapeutic intervention for patients with arthritis.

Arthritis, Rheumatoid↗
PubMed2001

Cyclooxygenase inhibition and thrombogenicity.

Cyclooxygenase (COX)-1 and COX-2 catalyze the formation of prothrombotic and antithrombotic eicosanoids, respectively. Aspirin, conventional nonsteroidal anti-inflammatory drugs (NSAIDs), and COX-2-specific inhibitors exhibit different patterns of inhibition of COX-1-mediated thromboxane biosynthesis and COX-2-mediated prostacyclin biosynthesis. The relationship between the pharmacologic inhibition of these vasoactive eicosanoids and the thromboprophylaxis or thrombogenicity exhibited by different therapeutic agents is currently unclear. Future studies are needed to assess the antithrombotic properties of commonly used NSAIDs, the hypothetical thrombogenicity of COX-2-specific inhibitors in high-risk patients, the need for concomitant aspirin with selective versus nonselective COX inhibitors, and the antiplatelet and gastric toxicity of the aspirin/COX-2-specific inhibitor combination in comparison with the aspirin/conventional NSAID combination.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Cognitive function in fibromyalgia patients.

OBJECTIVE: To evaluate fibromyalgia (FM) patients for the presence of cognitive deficits and to test the hypothesis that abnormalities would fit a model of cognitive aging. METHODS: We studied 3 groups of patients: FM patients without concomitant depression and in the absence of medications known to affect cognitive function (n = 23), age- and education-matched controls (n = 23), and education-matched older controls who were individually matched to be 20 years older (+/- 3 years) than the FM patients (n = 22). We measured speed of information processing, working memory function, free recall, recognition memory, verbal fluency, and vocabulary. We correlated performance on cognitive tasks with FM symptoms, including depression, anxiety, pain, and fatigue. We also determined if memory complaints were correlated with cognitive performance. RESULTS: As expected, older controls performed more poorly than younger controls on speed of processing, working memory, free recall, and verbal fluency. FM patients performed more poorly than age-matched controls on all measures, with the exception of processing speed. FM patients performed much like older controls, except that they showed better speed of processing and poorer vocabulary. Impaired cognitive performance in FM patients correlated with pain complaints, but not with depressive or anxiety symptoms. FM patients reported more memory problems than did the older and younger controls, and these complaints correlated with poor cognitive performance. CONCLUSION: Cognitive impairment in FM patients, particularly memory and vocabulary deficits, are documented in the study. Nevertheless, the intact performance on measures of information processing speed suggests that the cognitive deficits are not global. FM patients' complaints about their memory are likely to be legitimate, since their memory function is not age appropriate.

Aged↗
PubMed2001

Complementary and alternative therapies for fibromyalgia.

Fibromyalgia (FM) is a syndrome of chronic widespread musculoskeletal pain that is accompanied by sleep disturbance and fatigue. Clinical treatment usually includes lifestyle modifications and pharmacologic interventions meant to relieve pain, improve sleep quality, and treat mood disorders. These therapies are often ineffective or have been shown in clinical studies to have only short-term effectiveness. Pharmacologic treatments have considerable side effects. Patients may have difficulty complying with exercise-based treatments. Thus, patients seek alternative therapeutic approaches and physicians are routinely asked for advice about these treatments. This article reviews nontraditional treatment alternatives, from use of nutritional and herbal supplements to acupuncture and mind-body therapy. Little is known about efficacy and tolerance of complementary and alternative therapies in FM and other chronic musculoskeletal pain syndromes. Most studies on these treatments have been performed for osteoarthritis, rheumatoid arthritis, or focal musculoskeletal conditions. Clinical trials are scarce; the quality of these trials is often criticized because of small study population size, lack of appropriate control interventions, poor compliance, or short duration of follow-up. However, because of widespread and growing use of alternative medicine, especially by persons with chronic illnesses, it is essential to review efficacy and adverse effects of complementary and alternative therapies.

Complementary Therapies↗
PubMed2001

Prostaglandin biology.

PGs are important mediators of normal physiology, response to injury, and pathologic processes. Dissecting these biochemical and molecular pathways allows development of therapeutic agents that can be [figure: see text] applied to specific clinical situations, while preserving PGs that play a role in normal physiology.

Cyclooxygenase 1↗
PubMed2001

Polymyositis evolving after rhabdomyolysis associated with HMG-CoA reductase inhibitors: a report of two cases.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are commonly used for treatment of hyperlipidemia and its deleterious effects. Myotoxicity has been associated with use of these agents. We report two cases of inflammatory myopathy in patients receiving these agents that did not respond to drug withdrawal and required immunosuppressive treatment. One of these patients developed an antibody to histidyl tRNA synthetase or Jo-1, an autoantibody associated with idiopathic inflammatory myopathies. We suggest that HMG-CoA reductase inhibitor-associated myotoxicity may trigger an immune-mediated inflammatory myopathy. Patients whose muscle abnormalities do not resolve with drug withdrawal should be considered for muscle biopsy.

Journal Article↗
PubMed2001

Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis and other rheumatic diseases (April 2001).

TNF blocking agents have proved to be effective DMARDs and they have been a major advance in the treatment of RA. Their use is expanding to other rheumatic diseases. However, rare to uncommon and unexpected toxicities have been found and others may yet be found during their use. Studies in selected areas of efficacy, toxicity, and general use of TNF blocking agents are needed to help further define the most appropriate use of these agents. Use of these drugs will require doctors experienced in the diagnosis, treatment, and assessment of RA and other rheumatic diseases. These doctors will need to make long term observations of efficacy and toxicity. Further considerations which must be made when using TNF blocking agents in this disease include the cost and a recognition that data in subgroups are still being acquired. It is hoped that this statement, which is based upon the best evidence available at the time of its creation, and modified by expert opinion, will facilitate the optimal use of these agents for our patients with RA and other rheumatic diseases.

Antibodies, Monoclonal↗
PubMed2000

Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease.

Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents.

Animals↗
PubMed2000

Basic biology and clinical application of specific cyclooxygenase-2 inhibitors.

In summary, COX-2 is a highly regulated gene product that catalyzes the local production of PGs in pathologic and physiologic situations (Figure 1). It is clear that COX-2 is the isoform responsible for production of the PGs that mediate inflammation, pain, and fever. However, the role for COX-2 in normal physiology is still being defined. Specific COX-2 inhibitors represent a significant conceptual advance in therapy for patients with arthritis. Although there is no expectation of superior efficacy, clinical trials suggest that efficacy will be comparable with that of nonselective NSAIDs. Clinical trials demonstrate the potential for clinically meaningful reductions in the incidence of the most serious GI complications found with nonselective NSAIDs, i.e., ulcer, perforation, and GI bleeding. Over the next several years, treatment of large numbers of patients with specific COX-2 inhibitors will help to define the biology of COX-2. The magnitude of this advance in the therapy of rheumatic diseases is yet to be accurately determined, but the development of specific COX-2 inhibitors may afford significant new treatment options for many patients.

Cyclooxygenase 2↗
PubMed2000

Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors. A report of four cases.

Specific inhibitors of cyclooxygenase 2 (COX-2) have been approved for the treatment of osteoarthritis and rheumatoid arthritis. Unlike nonsteroidal anti-inflammatory drugs, specific COX-2 inhibitors do not inhibit platelet activation. However, these agents significantly reduce systemic production of prostacyclin. As a result, theoretical concerns have been raised that specific COX-2 inhibitors could shift the hemostatic balance toward a prothrombotic state. Patients with connective tissue diseases (CTD), who may be predisposed to vasculopathy and thrombosis, often have arthritis or pain syndromes requiring treatment with antiinflammatory agents. Herein we describe 4 patients with CTD who developed ischemic complications after receiving celecoxib. All patients had a history of Raynaud's phenomenon, as well as elevated anticardiolipin antibodies, lupus anticoagulant, or a history compatible with antiphospholipid syndrome. It was possible to measure a urinary metabolite of thromboxane A2 in 2 of the patients as an indicator of in vivo platelet activation, and this was markedly elevated in both. In addition, the patients had evidence of ongoing inflammation as indicated by elevated erythrocyte sedimentation rate, hypocomplementemia, and/or elevated levels of anti-DNA antibodies. The findings in these 4 patients suggest that COX-2 inhibitor-treated patients with diseases that predispose to thrombosis should be monitored carefully for this complication.

Adult↗
PubMed2000

Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome.

A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences. Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis. One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect. If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulating hormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.

Fatigue Syndrome, Chronic↗