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Biomedical subjects

L J Crofford

Publications and source records attributed to L J Crofford.

At least 37 records · Page 2Linked to original sources
PubMed2000

Clinical experience with specific COX-2 inhibitors in arthritis.

The common mechanism of action of aspirin and the chemically unrelated non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of prostaglandin (PG) production due to interference with the enzymatic activity of cyclooxygenase (COX). These agents have long been used as effective treatments for arthritis. The recognition that the inducible isoform COX-2 was associated with inflammation and arthritis led to the hypothesis that PGs produced by a COX-2-dependent pathway were responsible for the inflammation, pain, and tissue destruction. Since the constitutive COX-1 enzyme was identified as responsible for gastroprotection and inhibition of platelet function, the potential for compounds that were both effective and safer than NSAIDs led to rapid development of agents that specifically inhibit COX-2. These agents have now been tested and approved for use by the US Food and Drug Administration for patients with osteoarthritis and rheumatoid arthritis. They have been shown equally effective to comparitor NSAIDs. More importantly, there is a 3.5-fold reduction in the incidence of endoscopic gastroduodenal ulcerations and early data suggesting a similar reduction in clinically significant perforations, symptomatic ulcers, and bleeds. In patients with arthritis at risk for gastrointestinal complications of NSAIDs, specific inhibitors of COX-2 provide an effective and apparently safer form of anti-inflammatory agent.

Animals↗
PubMed2000

Follicular phase hypothalamic-pituitary-gonadal axis function in women with fibromyalgia and chronic fatigue syndrome.

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are clinically overlapping stress associated disorders. Neuroendocrine perturbations have been noted in both syndromes, and they are more common in women, suggesting abnormalities of gonadal steroid hormones. We tested the hypothesis that women with FM and CFS manifest abnormalities of the hypothalamic-pituitary-gonadal (HPG) hormonal axis. METHODS: We examined the secretory characteristics of estradiol, progesterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH), including a detailed analysis of LH in premenopausal women with FM (n = 9) or CFS (n = 8) during the follicular phase of the menstrual cycle compared to matched healthy controls. Blood was collected from an indwelling intravenous catheter every 10 min. over a 12 h period. LH was assayed from every sample; pulses of LH were identified by a pulse-detection program. FSH and progesterone were assayed from a pool of hourly samples for the 12 h period and estradiol from samples pooled over four 3 h time periods. RESULTS: There were no significant differences in FSH, progesterone, or estradiol levels in patients versus controls. There were no significant differences in pulsatile secretion of LH. CONCLUSION: There is no indication of abnormal gonadotropin secretion or gonadal steroid levels in this small, but systematic, study of HPG axis function in patients with FM and CFS.

Adolescent↗
PubMed1999

Central modulation of pain perception.

The information presented in this article provides a basis for individual variability in the sensation of pain and the behavioral correlates associated with pain. The knowledge of pain-inhibitory and pain-facilitating pathways linked to cognitive, emotional, and stress-response systems leads to a greater understanding of the complexities of the experience of pain. Appreciation of the influence of these higher centers should lead to improvements in the clinical management of pain.

Brain↗
PubMed1999

COX-2 in synovial tissues.

Prostaglandins (PGs) are important mediators of acute and chronic inflammation. The production of PGs in synovial tissues is catalyzed by an enzyme cascade that includes phospholipase A(2)s (PLA(2)s), cyclooxygenases (COXs), and terminal PG synthases. There are two isoforms of COX expressed in synovial tissues. COX-1 is constitutively expressed in synovia, particularly in synovial lining cells. COX-2, on the other hand, is localized most strikingly to the vascular endothelial cells, mononucler inflammatory cells, and subsynovial fibroblasts. There are no significant differences in immunostaining of COX-1 in vivo in inflammatory compared with non-inflammatory arthritis. COX-2 expression is increased in inflammatory arthritis. In-vitro, COX-2 expression in synovial cells is dramatically increased by proinflammatory cytokines, phorbol ester, and stimulation of certain cell surface receptors. A number of different transcription factors are likely to be involved in the up-regulation of COX-2 in synovial tissues. Expression of COX-2 is inhibited by glucocorticoids in synovial cells as in other cell types. Taken together, these data suggest that COX-2 is likely to be responsible for increased local PG production during inflammation of synovial tissues.

Arthritis↗
PubMed1999

Modeling the involvement of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes in autoimmune and stress-related rheumatic syndromes in women.

Autoimmune and stress-related rheumatic diseases are significantly more common in women than in men. Our group has focused on the role of two principal neuroendocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, in this increased susceptibility to rheumatic disease. We review the physiology of the HPA and HPG axes and discuss their reciprocal interactions. Mechanisms by which hormones of the HPA and HPG axes influence the immune system and modulate the course of autoimmune inflammatory diseases in animal models of rheumatic disease are described. In addition, we review the data suggesting the importance of these neurohormonal systems in rheumatic diseases. These data provide insights into why women may be at increased risk and how we might better understand the mechanisms that provoke expression of rheumatic diseases in women. To advance research in this area, it is critical to develop methods to evaluate the function of the neuroendocrine axes. Secretion of both HPA and HPG axis hormones, particularly the hormones of the hypothalamus and anterior pituitary, is largely by intermittent pulses. In addition, the HPA axis exhibits a profound circadian, or near 24-hour, variation, and HPG axis hormones fluctuate over the monthly cycle. These factors make meaningful analysis of these axes quite complex. We discuss models used in the analyses of neuroendocrine axes and the use of challenge testing to assess the integrity of neuroendocrine axes.

Animals↗
PubMed1999

Cyclooxygenase-2 expression in gastric antral mucosa before and after eradication of Helicobacter pylori infection.

OBJECTIVE: Helicobacter pylori (H. pylori) causes chronic gastritis. The inducible prostaglandin synthetase cyclooxygenase 2 (COX-2) plays an important role in inflammatory conditions. We hypothesized that H. pylori-associated chronic gastritis would express COX-2 protein. Our aim was to evaluate the effect of eradication of H. pylori infection on COX-2 expression in the antral mucosa of patients before and after antibiotic therapy. METHODS: Tissues were obtained from patients with non-ulcer dyspepia undergoing H. pylori eradication. Ten patients with proven H. pylori infection and subsequent successful eradication were studied. Three biopsies of antral mucosa were evaluated before and after H. pylori eradication. The amount of acute and chronic inflammation was quantitated. Immunohistochemical staining for COX-2 was expressed as a percentage of the total number of cells and correlated with the degree of chronic inflammation. RESULTS: Specific immunostaining for COX-2 was observed in antral mucosa of patients infected with H. pylori. Patchy cytoplasmic staining was seen in surface epithelial cells and strong cytoplasmic staining for COX-2 was seen in parietal cells. Spotty cytoplasmic staining for COX-2 was also seen in lamina propria plasma cells, as well as there being macrophages present in the germinal centers of lymphoid aggregates. COX-2 expression could be detected both before and after eradication of H. pylori. The mean percentage of cells staining for COX-2 was significantly higher in H. pylori-infected mucosa, compared with mucosa after successful H. pylori eradication (33.4% +/- 5.4 vs 18.9% +/- 3.3, p = 0.038). COX-2 immunostaining correlated best with the chronic inflammation score (r2 = 0.78, p < 0.001). There was a strong correlation for those subjects who were H. pylori infected, as well as for those who had successful H. pylori eradication. CONCLUSIONS: H. pylori associated acute and chronic antral inflammation was associated with immunohistochemical detection of COX-2 protein in epithelial cells, in addition to associated mononuclear cells and parietal cells. Expression was reduced, but not eliminated, in the epithelium after successful eradication of H. pylori. Despite the reduction in COX-2 expression after H. pylori eradication, expression of COX-2 in epithelial cells remained and strongly correlated with the extent of the chronic inflammatory cell infiltrate. The clinical implications of H. pylori-associated induction of COX-2 expression for patients on selective COX-2 inhibitors, in addition to the role of COX-2 in gastric carcinogenesis, deserve further study.

Acute Disease↗
PubMed1998

Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is characterized by profound fatigue and an array of diffuse somatic symptoms. Our group has established that impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis is an essential neuroendocrine feature of this condition. The relevance of this finding to the pathophysiology of CFS is supported by the observation that the onset and course of this illness is excerbated by physical and emotional stressors. It is also notable that this HPA dysregulation differs from that seen in melancholic depression, but shares features with other clinical syndromes (e.g., fibromyalgia). How the HPA axis dysfunction develops is unclear, though recent work suggests disturbances in serotonergic neurotransmission and alterations in the activity of AVP, an important co-secretagogue that, along with CRH, influences HPA axis function. In order to provide a more refined view of the nature of the HPA dusturbance in patients with CFS, we have studied the detailed, pulsatile characteristics of the HPA axis in a group of patients meeting the 1994 CDC case criteria for CFS. Results of that work are consistent with the view that patients with CFS have a reduction of HPA axis activity due, in part, to impaired central nervous system drive. These observations provide an important clue to the development of more effective treatment to this disabling condition.

Fatigue Syndrome, Chronic↗
PubMed1998

The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome.

HPA axis abnormalities in FM, CFS, and other stress-related disorders must be placed in a broad clinical context. We know that interventions providing symptomatic improvement in patients with FM and CFS can directly or indirectly affect the HPA axis. These interventions include exercise, tricyclic anti-depressants, and serotonin reuptake inhibitors. There is little direct information as to how the specific HPA axis perturbations seen in FM can be related to the major symptomatic manifestations of pain, fatigue, sleep disturbance, and psychological distress. Since many of these somatic and psychological symptoms are present in other syndromes that exhibit HPA axis disturbances, it seems reasonable to suggest that there may be some relationship between basal and dynamic function of the HPA axis and clinical manifestations of FM and CFS.

Adrenocorticotropic Hormone↗
PubMed1998

Neuroendocrine abnormalities in fibromyalgia and related disorders.

Fibromyalgia (FM) and related syndromes are poorly understood disorders that share symptoms such as pain, fatigue, sleep disturbances, and psychological distress. These syndromes are more common in women, and they are associated with psychological or physical stressors. The neuroendocrine axes are essential physiologic systems that allow for communication between the brain and the body. Interconnections among the neuroendocrine axes lead to coordinate regulation of these systems in both a positive and negative fashion. Several neuroendocrine axes have been shown to be dysfunctional in patients with FM. Although we do not yet understand the relationship between the reported disturbances of neuroendocrine function and the development or maintenance of FM and related syndromes, the authors have proposed that these abnormalities are important in symptomatic manifestations. This article reviews data showing disturbances of the neuroendocrine axes in FM and proposes a hypothesis of the development and maintenance of FM related to neuroendocrine disturbances.

Female↗
PubMed1998

Cyclical expression of GnRH and GnRH receptor mRNA in lymphoid organs.

Gonadotropin-releasing hormone (GnRH) is known to possess direct immunomodulatory effects. We have previously demonstrated that the administration of GnRH analogues modulates the expression of murine lupus independently of effects on gonadal steroids. We speculate that GnRH exerts direct actions at the level of the immune cells. GnRH receptors have been identified on lymphocytes. Because GnRH and GnRH receptor (GnRH-R) expression varies with the estrous cycle at the levels of the hypothalamus and pituitary, we speculated that similar cyclicity might be demonstrable in lymphoid tissue. In this report, we used competitive reverse transcription PCR to quantitate the expression of GnRH and GnRH-R mRNA in lymphoid organs throughout the estrous cycle in mice. We demonstrate that the pattern of expression of GnRH-R mRNA in spleen agrees closely with the pattern in the pituitaries of the same mice and the pattern previously reported in the rat pituitary, with significantly increased levels of expression seen on the afternoon of proestrus compared to the morning of metestrus. A similar pattern is seen with GnRH-R mRNA expression in the thymus. Furthermore, we show that the expression of GnRH mRNA in both thymus and spleen agrees closely with the pattern of expression of its receptor, with significantly increased levels of expression seen on the afternoon of proestrus compared to the morning of metestrus. Additional in vitro studies demonstrate that both GnRH and estradiol significantly increase the expression of GnRH-R mRNA in immune cells. These findings support an active role for GnRH in the immune system.

Animals↗
PubMed1998

Treatment of patients who have fibrodysplasia ossificans progressiva with isotretinoin.

Retinoids are a plausible family of therapeutic agents for fibrodysplasia ossificans progressiva due to their ability to inhibit differentiation of mesenchymal tissue into cartilage and bone. A prospective study was conducted to assess the efficacy of isotretinoin (13-cis-retinoic acid) in the prevention of heterotopic ossification in patients who had fibrodysplasia ossificans progressiva. Eleven anatomic regions were assessed in each of 21 patients by clinical examination, radiographs, and bone scans. An anatomic region was considered to be involved if there was clinical, radiographic, or radionuclide evidence of orthotopic or heterotopic ossification anywhere in the region. There were 143 involved anatomic regions and 88 uninvolved anatomic regions at the beginning of the study. Only one of the 88 anatomic regions that was completely uninvolved at the beginning of the study became involved during isotretinoin therapy. However, 16 of the 21 patients (76%) had major flare ups develop in 38 of 143 (27%) previously involved anatomic regions while administered isotretinoin therapy. Isotretinoin at steady state doses of 1 to 2 mg/kg per day decreased the incidence of heterotopic ossification at uninvolved anatomic regions compared with an external control group, as long as the medication was started before the appearance of any orthotopic or heterotopic ossification in that anatomic region. The data did not allow the determination of whether isotretinoin was effective or detrimental in preventing disease flareups in regions that had even minimal orthotopic or heterotopic ossification at the time the therapy began. Extreme caution should be exercised when using this medication in patients who have fibrodysplasia ossificans progressiva.

Adolescent↗
PubMed1997

Involvement of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression by interleukin-1 in rheumatoid synoviocytes.

OBJECTIVE: To evaluate involvement of the transcription factor nuclear factor kappa B (NF-kappa B) in the increased expression of cyclooxygenase-2 (COX-2) stimulated by interleukin-1 beta (IL-1 beta) in primary rheumatoid synoviocytes. METHODS: We treated early-passage rheumatoid synoviocytes with IL-1 beta and examined the time course of NF-kappa B translocation to the nucleus by Western blot analysis, as well as NF-kappa B binding to the COX-2 promoter/enhancer by electrophoretic mobility shift assay. We correlated the time course of NF-kappa B binding with expression of COX-2 messenger RNA (mRNA) and protein. Synoviocytes were then treated with either sense or antisense phosphorothioate-modified oligonucleotides derived from the transcription start site of the human NF-kappa B p65 RNA. We analyzed NF-kappa B binding to the COX-2 promoter and COX-2 protein levels after these treatments. RESULTS: IL-1 beta rapidly stimulated the translocation of the p65, p50, and c-rel NF-kappa B subunits from the cytoplasm to the nucleus. Electrophoretic mobility shift assay demonstrated binding to 2 NF-kappa B sites within the COX-2 promoter/enhancer, with a time course identical to that of nuclear localization of NF-kappa B. Supershift analysis revealed that binding activity was due primarily to the p65-p50 heterodimer and the p50 homodimer. With appropriate lag time after NF-kappa B binding, COX-2 mRNA and protein were increased. Pretreatment of RA synoviocytes with NF-kappa B p65 antisense oligonucleotides resulted in decreased binding to the COX-2 promoter and decreased COX-2 protein expression. CONCLUSION: These data demonstrate that signaling via the NF-kappa B pathway is involved in regulation of COX-2 expression induced by IL-1 beta in RA synoviocytes.

Arthritis, Rheumatoid↗
PubMed1997

Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis.

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.

Adrenocorticotropic Hormone↗
PubMed1997

COX-1 and COX-2 tissue expression: implications and predictions.

It has been proposed that cyclooxygenase (COX)-1 and COX-2 subserve different physiologic functions largely because of the striking differences in their tissue expression and regulation. COX-1 displays the characteristics of a "housekeeping" gene and is constitutively expressed in almost all tissues. COX-1 appears to be responsible for the production of prostaglandins (PG) that are important for homeostatic functions, such as maintaining the integrity of the gastric mucosa, mediating normal platelet function, and regulating renal blood flow. In sharp contrast, COX-2 is the product of an "immediate-early" gene that is rapidly inducible and tightly regulated. Under basal conditions, COX-2 expression is highly restricted; however, COX-2 is dramatically upregulated during inflammation. For example, synovial tissues in patients with rheumatoid arthritis (RA) express increased levels of COX-2. In animal models of inflammatory arthritis, COX-2 increases in parallel with PG production and clinical inflammation. In vitro experiments have revealed increased COX-2 expression after stimulation with proinflammatory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), in many cell types, including synoviocytes, endothelial cells, chondrocytes, osteoblasts, and monocytes/macrophages. Another distinguishing characteristic of COX-2 is decreased expression in response to glucocorticoids. COX-2 is also increased in some types of human cancers, particularly colon cancer. Mechanisms underlying the association between COX-2 overexpression and tumorigenic potential may include resistance to apoptosis, or programmed cell death. Upregulated COX-2 expression undoubtedly plays a role in pathologic processes characterized by increased local PG production. One would predict, based on current information regarding the differential tissue expression of COX-1 and COX-2, that highly selective inhibitors of COX-2 will provide effective antiinflammatory activity with marked reduction in toxicity.

Animals↗
PubMed1996

Responsiveness of human T lymphocytes to bacterial superantigens presented by cultured rheumatoid arthritis synoviocytes.

OBJECTIVE: Type B fibroblastic synoviocytes are abundant in inflamed joints of patients with rheumatoid arthritis (RA), and can secrete cytokines and other mediators of inflammation. The aim of this study was to determine whether cell lines derived from RA type B synoviocytes could also serve as accessory cells for T lymphocyte activation. METHODS: Cells from RA synoviocyte lines, with or without preculture in interferon-gamma (IFN gamma), were cultured with purified peripheral blood T cells, in the presence or absence of superantigens or other accessory cell-dependent T cell mitogens. T cell proliferation was measured by thymidine incorporation, and synoviocyte surface markers were analyzed by flow cytometry. RESULTS: RA type B synoviocyte lines were potent accessory cells for T cell responses to bacterial superantigens or lectins, and direct cell-cell contact was required. Preculture in IFN gamma augmented synoviocyte expression of major histocompatibility complex (MHC) class II molecules and of ligands for some T cell costimulatory receptors, but synoviocyte accessory cell function was evident even in the absence of IFN gamma. Blocking studies using monoclonal antibodies supported the notion of a role CD2, CD11a/CD18 and MHC class II molecules in synoviocyte-dependent T cell activation. Monoclonal antibodies against IFN gamma, interleukin-1 beta (IL-1 beta), IL-6, IL-8, and tumor necrosis factor alpha failed to block the T cell proliferative responses, but anti-IL-2 was strongly inhibitory. CONCLUSION: Cultured RA and type B synoviocytes can perform some of the functions of professional antigen-presenting cells. If such cells have similar properties in vivo, they may be important participants in activation of immune responses, in addition to their previously described synthetic and proinflammatory roles. If RA synovial tissue T cells, like normal peripheral blood T cells, can respond to superantigens presented by synoviocytes, this interaction could be important in the pathogenesis of RA.

Antigens, CD↗
PubMed1996

Evidence that abnormalities of central neurohormonal systems are key to understanding fibromyalgia and chronic fatigue syndrome.

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) fall into the spectrum of what might be termed stress-associated syndromes by virtue of frequent onset after acute or chronic stressors and apparent exacerbation of symptoms during periods of physical or emotional stress. These illnesses also share perturbation of the hypothalamic-pituitary-adrenal axis and sympathetic stress response systems. In this article, the authors discuss the specific neurohormonal abnormalities found in FM and CFS and potential mechanisms by which dysfunction of neurohormonal stress-response systems could contribute to vulnerability to stress-associated syndromes and to the symptoms of FM and CFS.

Humans↗