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ID PMID Title PublicationDate abstract
11940315 [Clinical characteristics of primary biliary cirrhosis: a report of 45 cases]. 2002 Mar OBJECTIVE: To study the clinical features of primary biliary cirrhosis (PBC) in order to facilitate cognition of the disease. METHODS: General status, clinical manifestations and laboratory findings of 45 patients with PBC were reviewed. RESULTS: Among the 45 patients, 42 were females and the mean age at diagnosis was (50.8 +/- 8.1) years. The mean time interval between the first visit to physicians to the time of correct diagnosis was about 2 years. The most frequent symptoms were fatigue (66.7%, 30/45), then jaundice (55.6%, 25/45) and pruritus (40%, 18/45). Nine patients (20%) were asymptomatic. Nine patients (20%) were associated with other auto-immune diseases (Sjogren's syndrome and/or rheumatoid arthritis). Serum alkaline phosphatase (ALP) and glutamyl transpeptidase (gamma-GT) levels were markedly elevated in all the patients [(498.5 +/- 369.8) IU/L and (595.2 +/- 518.4) IU/L, respectively], whereas ALT and AST levels were mildly to moderately elevated [(83.9 +/- 58.8) IU/L and (100.8 +/- 48.8) IU/L, respectively]. 25 patients (55.6%) had a total bilirubin level >/= 34.2 micromol/L. 40 patients (88.9%) had elevated serum IgM and 43 patients (95.6%) were anti-mitochondrial antibody (AMA)/AMA-M2 positive. CONCLUSION: In China, PBC is probably not so rare as it was thought before. It is mostly found in middle-aged women. The most frequent symptom is fatigue and some patients are asymptomatic at early stage. Elevated serum ALP and gamma-GT levels together with positive AMA/AMA-M2 can help to diagnose PBC. Liver biopsy is useful to confirm the diagnosis and differentiate histopathological stages.
14558048 Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and 2003 Oct 15 OBJECTIVE: To analyze specific clinical findings, underlying disorders, treatments, outcomes, and prognostic factors for reactive hemophagocytic syndrome (RHS) in systemic disease. METHODS: Data were collected using standardized forms as part of a French national survey. Adult cases without an underlying malignancy, diagnosed on bone marrow or lymph node biopsy, were included. RESULTS: Twenty-six cases (7 men, 19 women, mean age 47.4 +/- 17.7 years) were studied. Systemic diseases included systemic lupus erythematosus (n = 14), rheumatoid arthritis (n = 2), adult onset systemic Still's disease (n = 4), polyarteritis nodosa (n = 2), mixed connective tissue disease (n = 1), pulmonary sarcoidosis (n = 1), systemic sclerosis (n = 1), and Sjögren's syndrome (n = 1). RHS occurred in 2 distinct clinical settings in the course of systemic disease. RHS was associated with an active infection in 15 patients (bacterial infections, 10 cases; viral, 3 cases; tuberculosis, 1 case; and aspergillosis, 1 case) and with the onset of a systemic disease alone in 9 cases. Isolated RHS occurred in 2 cases. The overall mortality rate was 38.5%. Two factors were associated with mortality: corticosteroid treatment at the time of RHS diagnosis, and thrombocytopenia (odds ratio = 28, 95% confidence interval = 13.3-238.9). CONCLUSIONS: When RHS occurs in the course of an active systemic disease (situation only reported in cases of systemic lupus or adult Still's disease), immunosuppressive therapy should be used. In contrast, when RHS is present concomitantly with an active infection, immunosuppressive therapy needs to be lowered and antibiotic therapy should be instituted.
12906745 Rofecoxib: an update on physicochemical, pharmaceutical, pharmacodynamic and pharmacokinet 2003 Jul Rofecoxib (MK-966) is a new generation non-steroidal anti-inflammatory agent (NSAID) that exhibits promising anti-inflammatory, analgesic and antipyretic activity. It selectively inhibits cyclooxygenase (COX)-2 isoenzyme in a dose-dependent manner in man. No significant inhibition of COX-1 is observed with rofecoxib up to doses of 1000 mg. The pharmacokinetics of rofecoxib has been found to be complex and variable. Mean oral bioavailability after single dose of rofecoxib (12.5, 25 or 50 mg) is 93% with t(max) varying widely between 2 and 9 h. It is highly plasma-protein bound and is metabolized primarily by cytosolic reductases to inactive metabolites. Rofecoxib is eliminated predominantly by hepatic metabolism with a terminal half-life of approximately 17 h during steady state. Various experimental models and clinical studies have demonstrated rofecoxib to be superior, or at least equivalent, in anti-inflammatory, analgesic and antipyretic efficacy to comparator nonselective NSAIDs in osteoarthritis, rheumatoid arthritis and other pain models. Emerging evidence suggests that rofecoxib may also find potential use as supportive therapy in various pathophysiologic conditions like Alzheimer's disease, and in various malignant tumours and polyps, where COX-2 is overly expressed. Rofecoxib is generally well-tolerated. Analysis of data pooled from several trials suggests that rofecoxib is associated with fewer incidences of clinically symptomatic gastrointestinal ulcers and ulcer complications vis-à-vis conventional NSAIDs. However, this gastropreserving effect may be negated by concurrent use of low-dose aspirin for cardiovascular risk reduction. Rofecoxib tends to show similar tolerability for renal and cardiothrombotic events as compared with nonnaproxen nonselective NSAIDs. No clinically significant drug interaction has been reported for rofecoxib except with diuretics, where it reverses their salt-wasting effect and thus can be clinically exploited in electrolyte-wasting disorders. There is only modest information about the physicochemical and pharmaceutical aspects of rofecoxib. Being poorly water soluble, its drug delivery has been improved using varied formulation approaches. Although it is stable in solid state, rofecoxib is photosensitive and base-sensitive in solution form with its degradation mechanistics elucidated. Analytical determinations of rofecoxib and its metabolites in biological fluids employing HPLC with varied types of detectors have been reported. Isolated studies have also been published on the chromatographic and spectrophotometric assay of rofecoxib and its degradants in bulk samples and pharmaceutical dosage forms. The current article provides an updated overview on the physicochemical, pharmaceutical, pharmacokinetic and pharmacodynamic vistas of rofecoxib.
12854675 Surgeon training and complications in total ankle arthroplasty. 2003 Jun BACKGROUND: This study assessed the problems with initial use of ankle arthroplasty by surgeons who were trained by observing the surgeon/inventor (group I), who have completed a structured, hands-on surgical training course (group II), or who were trained during a 1-year foot and ankle fellowship (group III). MATERIALS AND METHODS: The perioperative records of the first 10 cases of nine surgeons were reviewed. We evaluated the 6-month-postoperative standing mortise and lateral radiographs for evidence of syndesmosis union and accuracy of tibial component implantation. Three surgeons were each in group I, group II, and group III. Average patient age at time of surgery was similar. Ankle arthritis was classified as rheumatoid arthritis (RA) or osteoarthritis (OA) as follows: group I (7 RA, 23 OA), group II (7 RA, 23 OA), and group III (3 RA, 27 OA). RESULTS: In group I, there were nine intraoperative complications, four postoperative wound dehiscences, and three postoperative deep infections. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 10/26 (38%) had a delayed union of the syndesmosis. In group II, there were six intraoperative complications and two postoperative wound problems: an early anterior wound problem and a delayed lateral wound breakdown. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 13/26 (50%) had a delayed union of the syndesmosis. In group III, there were four intraoperative complications and four postoperative wound problems--all healed with local supportive care with one requiring lateral hardware removal. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 5/30 (17%) had a delayed union of the syndesmosis. The initial series from these three groups are statistically indistinguishable with respect to rates of complications, revisions, or malalignment. CONCLUSION: No identified training method had a statistically demonstrable positive impact on preparing surgeons for performing total ankle replacement. Some of these findings are likely generic for total ankle replacements and not restricted to any class or design of implant. Surgeon initial use of total ankle replacement needs to be done with caution and serious consideration.
15221489 The active metabolite of leflunomide, A771726, inhibits both the generation of and the bon 2004 Leflunomide is a disease-modifying antirheumatic drug that inhibits paw swelling and joint destruction in type II collagen-induced arthritis in mice and it also delays disease progression in patients with rheumatoid arthritis (RA), through inhibiting proliferation and cytokine production of T cells, via the blocking of de-novo pyrimidine biosynthesis by its active metabolite, A771726. However, the direct action of leflunomide on cells of osteoclast lineage responsible for bone destruction in RA remains to be clarified. In this study, we examined the effect of A771726 on osteoclast formation and bone-resorbing activity in vitro, using cultures of bone marrow-derived osteoclast progenitors and purified functionally mature osteoclasts, and then we elucidated the molecular mechanism of action of the effect of A771726 on osteoclasts. A771726 inhibited osteoclast formation from macrophage colony-stimulating factor (M-CSF)-dependent osteoclast progenitors in the presence of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL), without any other types of cells present, in a dose-related manner, similar to the inhibition in cultures of unfractionated bone marrow cells. In addition, A771726 suppressed bone resorption by isolated mature osteoclasts. These results indicate that A771726 directly and intrinsically inhibited the differentiation and function of osteoclast lineage cells without any mediation by other cells. The inhibition by A771726 was not restored by the simultaneous addition of uridine, and may be independent of the blockade of NF-kappaB activation and the tyrosine phosphorylation of proteins. Thus, leflunomide, through its active metabolite, has the potential to prevent bone loss by directly inhibiting osteoclastogenesis and osteoclast function. This inhibition suggests a novel mechanism for leflunomide in the retardation of the joint destruction observed in RA patients.
12905473 High binding capacity of cyclophilin B to chondrocyte heparan sulfate proteoglycans and it 2003 Aug OBJECTIVE: To study cyclophilin B, a protein newly identified as a secretion product of cultured chondrocytes, in the context of chondrocyte pathobiology. METHODS: Cyclophilin B was purified by sequential chromatographic processing of the secretion medium of cultured guinea pig chondrocytes. Its presence both at the surface of chondrocyte monolayers and in cartilage was demonstrated by immunohistochemistry. Binding sites at the surface of chondrocytes were characterized by Scatchard plot analysis using (125)I-labeled cyclophilin B, and by glycosidase treatments. The release of cyclophilin B from chondrocytes by activated matrix metalloproteinases (MMPs) was studied by Western blot analysis. RESULTS: Cyclophilin B was present at the surface of cultured chondrocytes and within cartilage, both in cells and in the extracellular matrix, with a particularly intense staining in the superficial layer. It was secreted constitutively by chondrocytes and cartilage explants. Its secretion was enhanced after treatment with its pharmacologic binding partner, cyclosporin A (CSA). Experiments with (125)I-labeled cyclophilin B demonstrated the presence of high-capacity, low-affinity, NaCl-sensitive binding sites at the surface of chondrocytes. Cell-bound cyclophilin B could be released by heparinase treatment, demonstrating binding to pericellular heparan sulfate proteoglycans (HSPGs). Chondroitinase or keratanase treatments had no effect. MMPs 1, 2, 3, 9, and 13 released intact cyclophilin B from the cell surface, probably by cleavage of HSPGs. This effect was reversed by the broad-spectrum MMP inhibitor, marimastat. CONCLUSION: Cyclophilin B is a secreted CSA-binding protein involved in inflammatory events. It can induce chemotaxis in human neutrophils and T lymphocytes. The finding that cyclophilin B is an intrinsic component of cartilage and that it can be released by MMPs suggests that it has a role in the pathogenesis of arthritic diseases, even more so since its signaling receptor is present within the inflamed joint both on T cells and in the rheumatoid synovium.
14674013 Development of autoimmune exocrinopathy resembling Sjögren's syndrome in adoptively trans 2003 Dec OBJECTIVE: The pathologic mechanisms responsible for organ-specific tissue damage in primary Sjögren's syndrome (SS) remain unclear, but it has been suggested that the pathology is mediated by autoreactive CD4+ T cells infiltrating the salivary and lacrimal glands. This study was undertaken to investigate whether alpha-fodrin autoantigen-specific autoreactive CD4+ T cells are capable of inducing autoimmune lesions. METHODS: A total of 45 synthetic alpha-fodrin peptides designed to be 20 amino acid residues in length were generated. To establish an autoreactive T cell line, limiting dilution analysis (LDA) was performed on lymph node cells (LNCs) in the presence of alpha-fodrin peptides. The effects of adoptive transfer of autoreactive CD4+ T cells into normal syngeneic recipients were investigated. RESULTS: Autoreactive CD4+ T cell lines that recognize synthetic alpha-fodrin peptide, which produced Th1 cytokines and showed cytotoxic activities, were established in a murine model for SS. T cell receptor V(beta) usage and third complementarity-determining region (CDR3) sequences indicated that in some cases V(beta)6-CDR3 genes matched between the tissue-infiltrating T cells and the autoreactive T cell lines. Adoptive transfer of the autoreactive CD4+ T cells into normal syngeneic recipients induced autoimmune lesions quite similar to those of SS. CONCLUSION: Our data help to elucidate the pathogenic mechanisms responsible for tissue destruction in autoimmune exocrinopathy and indicate that autoreactive CD4+ T cells play a pivotal role in the development of murine SS.
14613282 Cellular basis of ectopic germinal center formation and autoantibody production in the tar 2003 Nov OBJECTIVE: To investigate functional properties of the germinal center (GC)-like structures observed in salivary glands of patients with Sjögren's syndrome (SS) and to determine the frequency with which such structures develop. METHODS: Hematoxylin and eosin-stained sections from 165 minor salivary gland biopsy samples were screened for GC-like structures. Expression of markers for GCs (CD3, CD20, Ki-67, CD35, CD31), adhesion molecules (intercellular adhesion molecule 1, lymphocyte function-associated antigen 1, vascular cell adhesion molecule 1, very late activation antigen 4), chemokines (CXCL13, CCL21, CXCL12), and production of autoantibodies (anti-Ro/SSA and anti-La/SSB) was investigated by immunohistochemistry. Apoptosis was investigated by TUNEL staining. RESULTS: GC-like structures were observed in 28 of 165 patients (17%). When GCs were defined as T and B cell aggregates with proliferating cells with a network of follicular dendritic cells and activated endothelial cells, such microenvironments were found in all patients in whom structures with GC-like morphology were observed. The defined microenvironments were not found in patients without apparent GC-like structures. The GCs formed within the target tissue showed functional features with production of autoantibodies (anti-Ro/SSA and anti-La/SSB) and apoptotic events (by TUNEL staining), and the local production of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly increased (P = 0.04) in patients with GC development. CONCLUSION: Lymphoid neogenesis and functional ectopic GC formation take place in salivary glands of a subset of patients with SS. Our data suggest that the ectopic secondary lymphoid follicles contain all elements needed for driving the autoimmune response. Our findings underscore a key role for the target organ in recruitment of inflammatory cells and propagation of the disease process.
14574658 A simple and rapid approach to hypokalemic paralysis. 2003 Oct Hypokalemia with paralysis (HP) is a potentially reversible medical emergency. It is primarily the result of either hypokalemic periodic paralysis (HPP) caused by an enhanced shift of potassium (K(+)) into cells or non-HPP resulting from excessive K(+) loss. Failure to make a distinction between HPP and non-HPP could lead to improper management. The use of spot urine for K(+) excretion rate and evaluation of blood acid-base status could be clinically beneficial in the diagnosis and management. A very low rate of K(+) excretion coupled with the absence of a metabolic acid-base disorder suggests HPP, whereas a high rate of K(+) excretion accompanied by either metabolic alkalosis or metabolic acidosis favors non-HPP. The therapy of HPP requires only small doses of potassium chloride (KCl) to avoid rebound hyperkalemia. In contrast, higher doses of KCl should be administered to replete the large K(+) deficiency in non-HPP.
12114274 Androgen deficiency, Meibomian gland dysfunction, and evaporative dry eye. 2002 Jun OBJECTIVE: We have recently discovered that women with primary and secondary Sjögren's syndrome are androgen-deficient. We hypothesize that this hormone insufficiency contributes to the meibomian gland dysfunction, tear film instability, and evaporative dry eye that are characteristic of this autoimmune disorder. If our hypothesis is correct, we predict: (1) that androgens regulate meibomian gland function, control the quality and/or quantity of lipids produced by this tissue, and promote the formation of the tear film's lipid layer; and (2) that androgen deficiency, due to an attenuation in androgen synthesis (e.g., during Sjögren's syndrome, menopause, aging, complete androgen-insensitivity syndrome [CAIS] and anti-androgen use), will lead to meibomian gland dysfunction and evaporative dry eye. The following studies were designed to test these predictions. METHODS: Experimental procedures included clinical studies, animal models, and histological, biochemical, molecular biological, and biomedical engineering techniques. RESULTS: Our results demonstrate that: (1) androgens regulate the meibomian gland. This tissue contains androgen receptor mRNA, androgen receptor protein within acinar epithelial cell nuclei, and Types 1 and 2 5alpha-reductase mRNAs. Moreover, androgens appear to modulate lipid production and gene expression in mouse and/or rabbit meibomian glands; and (2) androgen deficiency may lead to meibomian gland dysfunction, altered lipid profiles in meibomian gland secretions, tear film instability, and evaporative dry eye. Thus, we have found that anti-androgen therapy in men is associated with meibomian gland disease, a decreased tear film breakup time, and functional dry eye. Furthermore, we have discovered that androgen receptor dysfunction in women with CAIS is associated with meibomian gland changes and a significant increase in the signs and symptoms of dry eye. Of interest, we have also found that androgen deficiency is associated with significant and striking alterations in the neutral and polar lipid patterns of human meibomian gland secretions. CONCLUSIONS: Our findings show that the meibomian gland is an androgen target organ and that androgen deficiency may promote meibomian gland dysfunction and evaporative dry eye. Overall, these results support our hypothesis that androgen deficiency may be an important etiologic factor in the pathogenesis of evaporative dry eye in women with Sjögren's syndrome.
15037117 ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patie 2004 Apr PURPOSE: We previously reported that immune-based inflammation occurs on the ocular surface of humans as well as canines with keratoconjunctivitis sicca (KCS). Intercellular adhesion molecule-1 (ICAM-1) was found to be upregulated on lymphocytes and/or vascular endothelial cells resulting in lymphocytic diapedesis to the lacrimal and conjunctival tissues. The purpose of the current study was to demonstrate the role of ICAM-1 in (1) resident epithelial cell response during ocular inflammation, (2) local and/or peripheral lymphocyte activation or accumulation in the ocular tissues, and (3) whether anti-ICAM-1 is effective to attenuate immune-mediated ocular inflammation. METHODS: ICAM-1 levels in various ocular tissues of human with KCS and/or MRL/lpr mouse were evaluated by immunohistochemistry and in situ hybridization for protein and messenger RNA (mRNA) expression, respectively. Soluble ICAM-1 concentrations in MRL/lpr mouse plasma over the course of disease development were measured by ELISA. Cell proliferation within ocular tissues was assessed by bromodeoxyuridine (BrdU) incorporation and immunohistochemical detection. The level of T cell activation was determined by IL-2 receptor (CD25, a marker of T cell activation and proliferation) and CD69 (a marker of T cell activation) immunoreactivity using FACS analysis. To examine the effectiveness of anti-ICAM-1/LFA-1 in elimination of lacrimal gland inflammation, MRL/lpr mice were injected intraperitoneally (i.p.) with or without monoclonal antibodies against ICAM-1 and LFA-1 at three or eight weeks of age. RESULTS: Increased endogenous ICAM-1 expression at the level of protein and mRNA was detected in the epithelial cells present in the conjunctival and accessory lacrimal tissues in dry eye patients. In MRL/lpr mice, ICAM-1 expression by lacrimal acinar epithelial cells and conjunctival epithelial cells were detected in addition to inflammatory infiltrates and vascular endothelial cells at 16 weeks of age. Soluble ICAM-1 levels were markedly increased concomitantly with disease progression over time as compared with the controls. No significant lymphocytic proliferation (a lack of BrdU and CD25 immunoreactivities) was detected within lacrimal glands of MRL/lpr mice at the disease onset. However, a population of the infiltrated T cells were CD69 positive, indicating the activation stage of a T cell subset. Treatment using monoclonal antibodies against murine ICAM-1 and LFA-1 resulted in a decrease in the number of inflammatory infiltrates in MRL/lpr mice. CONCLUSIONS: Our findings suggest that ICAM-1 upregulation locally and systemically promote lymphocyte activation and migration to the ocular surface (OS). Ocular resident epithelium is an active component of ocular surface and is capable of interacting with invasive lymphocytes by ICAM-1 production in response to immune activation and inflammation. ICAM-1 synthesized by epithelial cells may serve as a signaling molecule for predisposition of ocular surface inflammation and facilitate potential antigen presentation by epithelial cells. Lymphocytic infiltrates in the lacrimal gland of the MRL/lpr mouse appeared to be the result of the accumulation, but not proliferation of circulating lymphocytes diapodesed from the vasculature that had migrated into the local ocular tissues. The potential use of anti-ICAM-1 therapy in treating immune-based inflammatory diseases such as dry eye deserves further investigation.
14679981 [Bilateral swelling of the parotid glands as part of a systemic disease]. 2003 Nov 22 In four patients, a man aged 34 years and three women aged 35, 32 and 55 years respectively bilateral swelling of the parotid glands was caused by systemic disease i.e. HIV-salivary gland disease, mucosa-associated lymphoid-tissue (MALT) lymphoma, sarcoidosis with coexisting Sjögren's syndrome, and sialosis and hypothyroidism, respectively. The HIV patient was treated with antiretroviral therapy, the first two women were treated expectantly and the third woman was given a thyroid hormone supplement which resulted in regression of the bilateral parotid enlargement. Bilateral enlargement of the parotid glands is not necessarily caused by infection, it can also be of systemic origin. Minimal invasive investigations of the salivary glands, such as sialography, measurement of salivary secretion rate (sialometry) and analysis of salivary composition (sialochemistry) can offer valuable information about the origin of the parotid gland swelling. Histopathological investigation of an incision biopsy of the parotid gland is an easy way to confirm the diagnosis. The morbidity associated with parotid biopsy is negligible.
14563019 Presence of B7-2+ dendritic cells and expression of Th1 cytokines in the early development 2003 Jun Subpopulations of infiltrating lymphocytes, professional antigen-presenting cells (APCs), and Th1/Th2 cytokines that could initiate an autoimmune sialodacryoadenitis were studied in the IQI/Jic mouse model of primary Sjögren's syndrome. Although lymphocytic infiltrations were first seen in submandibular glands (SMGs) of females and in lacrimal glands (LGs) of males at 8 weeks of age, clusters of MHC class II+, CD11c+, B7-2+ dendritic cells (DCs) were already localized in these tissues at 4 weeks. At 8 weeks, the infiltrating lymphocytes consisted of almost equal numbers of B cells and CD4+ T cells. In the inflammatory foci, MHC class II+, CD11c+, B7-2+ DCs formed network-like structures. Duct cells in the lesions showed immunoreactivities for MHC class II and ALCAM (a costimulatory adhesion molecule). IL-12 and IFN-gamma transcripts were detected by RT-PCR in SMGs of females and in LGs of males at 8-12 weeks. These results suggest that the clustered DCs might play an important role in the initiation of the adenitis, and further suggest that the DCs and epithelial cells may participate in the activation of CD4+ T cells. It is also likely that Th1 cytokines mediate the functional interactions between the APCs and CD4+ T cells in the early lesions.
12044983 Role of anti-calcium channel and anti-receptor autoantibodies in autonomic dysfunction in 2002 Jun Auto-antibodies cross-reacting with L-type voltage-gated calcium channels (VGCCs) have been described in primary Sjögren's syndrome (pSS), and may mediate the cardiac defects in neonates born to mothers with pSS. L-type VGCCs are also present in autonomically innervated tissues. Therefore, the aim of this project was to investigate a role for anti-VGCC antibodies and antibodies to alpha(1)-adrenoceptors or P(2X)-purinoceptors in the autonomic dysfunction that occurs in pSS. Contraction of the sympathetically innervated vas deferens in response to stimulation of the muscle by an alpha(1)-adrenoceptor agonist (phenylephrine) or a P(2X)-purinoceptor agonist (alpha,beta-methylene ATP) was measured in the absence and presence of 2% serum. Contractions produced by phenylephrine and by alpha,beta-methylene ATP were abolished by nicardipine, demonstrating that they are coupled to calcium influx through L-type VGCCs. Serum from patients with pSS or from healthy controls did not significantly alter the L-type channel-dependent responses of smooth muscle to agonist stimulation. We therefore conclude that pSS serum does not contain autoantibodies that functionally inhibit L-type VGCCs, alpha(1)-adrenoceptors or P(2X)-purinoceptors in smooth muscle and that such autoantibodies cannot explain the autonomic dysfunction in pSS.
14507655 Development of autoimmune exocrinopathy resembling Sjögren's syndrome in estrogen-deficie 2003 Oct Although a number of autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear. We speculate that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens. Previously, we have identified 120-kd alpha-fodrin as an important autoantigen in Sjögren's syndrome (SS). When healthy C57BL/6 (B6) mice were treated with an ovariectomy (Ovx), we found a significant increase in TUNEL(+)-apoptotic epithelial cells in the salivary gland cells associated with alpha-fodrin cleavage during 2 and 3 weeks after Ovx. By contrast, no apoptotic cells were found in estrogen receptor-alpha knockout mice. In in vitro studies using primary cultured mouse salivary gland cells and human salivary gland cells, we found a cleavage product of 120-kd alpha-fodrin in cells that had undergone tamoxifen (Tam)-induced apoptosis through caspase activation, especially caspase-1. Adoptive transfer of alpha-fodrin-reactive T cells into Ovx-B6 and -SCID mice resulted in the development of autoimmune exocrinopathy quite similar to SS. These results suggest that estrogen deficiency exerts a crucial influence on autoantigen cleavage, and may cause, in part, autoimmune exocrinopathy in postmenopausal women.
15254347 Diminished cellular immune response to carbonic anhydrase II in patients with Sjögren's s 2004 Jul CONTEXT: A serum antibody to carbonic anhydrase II has been reported in patients with Sjögren's syndrome and idiopathic chronic pancreatitis. OBJECTIVE: To evaluate cellular immune response to carbonic anhydrase II in patients with Sjögren's syndrome and idiopathic chronic pancreatitis. PATIENTS: Idiopathic chronic pancreatitis (n=23), Sjögren's syndrome (n=12), alcoholic chronic pancreatitis (n=3) and normal controls (n=13). MAIN OUTCOME MEASURES: Proliferation assay of peripheral blood mononuclear cells. RESULTS: Notable increased proliferation of the mononuclear cells upon stimulation with carbonic anhydrase II was observed in 2 patients with idiopathic chronic pancreatitis (9%) and 2 patients with Sjögren's syndrome (17%) but not in patients with alcoholic chronic pancreatitis nor in normal controls. Among the four study groups, there was no significant difference in the prevalence rate of the positive proliferative responses (P=0.444). CONCLUSION: Carbonic anhydrase II may not be a major target antigen for the immunological process in the pathogenesis of Sjögren's syndrome and idiopathic chronic pancreatitis. Serum antibody to carbonic anhydrase II may be detected in these patients as a consequence of the immune reaction against other antigens which mimic carbonic anhydrase II.
15095277 Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients wit 2004 Apr Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by lymphocytic infiltration of the salivary glands. Most of the infiltrating cells are T cells, but other features of the disease include polyclonal B-cell activation, systemic production of autoantibodies, and increased risk of developing B-cell non-Hodgkin's lymphoma. Recently, a new tumour necrosis factor, the B-cell activating factor (BAFF; also known as BLyS), has been implicated in the polyclonal activation of B cells. Using immunohistochemistry, this study evaluated BAFF expression in labial salivary gland biopsies from 14 patients with pSS, 14 normal controls, and two patients with sarcoidosis. Labial salivary gland samples from seven patients with pSS, seven controls, and one patient with sarcoidosis were double-stained using indirect immunofluorescence. RT-PCR analysis was also performed on lip biopsy samples from two patients and two controls. In all 14 pSS specimens, infiltrating inflammatory cells strongly expressed BAFF protein, as did some ductal epithelial cells, but acinar cells were negative. Some B cells were present in the vicinity of the BAFF-positive cells. In the 14 normal labial salivary glands, some ductal cells were moderately positive, but acinar cells were negative. In the labial salivary glands from the two patients with sarcoidosis, infiltrating lymphocytes were not stained. BAFF mRNA expression was confirmed by RT-PCR in salivary glands from pSS patients. Double immunofluorescence revealed T cells and macrophages to be the main cell types expressing BAFF in salivary glands from pSS patients. In conclusion, BAFF may be expressed by T cells at the site of autoimmune damage and could play a role in the pathogenesis of pSS, particularly by triggering the activation of self-antigen-driven autoimmune B cells.
12147592 Conjunctival T-cell subpopulations in Sjögren's and non-Sjögren's patients with dry eye. 2002 Aug PURPOSE: To examine the conjunctiva of patients with Sjögren's syndrome keratoconjunctivitis sicca (SS-KCS) and non-Sjögren's keratoconjunctivitis sicca (NS-KCS) for evidence of immune-based inflammation. METHODS: Conjunctival biopsy specimens were obtained from 15 patients with SS-KCS and 15 with NS-KCS. Immunohistochemistry was performed on frozen sections to characterize and quantify T-cell subtypes (CD3, CD4, and CD8) and markers of immune activation (major histocompatibility complex [MHC] class II: HLA-DR, HLA-DQ) and inflammation (intercellular adhesion molecule [ICAM]-1). The numbers of cells positive for each marker were counted by two masked observers and averaged. RESULTS: Conjunctival biopsy specimens from patients with SS-KCS or NS-KCS revealed lymphocytic infiltration and increased immunoreactivity for the markers of inflammation and immune activation. The extent of cellular immunoreactivity did not differ significantly between SS-KCS and NS-KCS tissue samples. CONCLUSIONS: The authors' findings indicate that patients with SS-KCS or NS-KCS have conjunctival inflammation manifested by inflammatory cell infiltrates and upregulation of expression in markers of immune activation. Clinical symptoms of KCS may be more dependent on T-cell activation and resultant inflammation than previously believed. In addition to tear substitutes, anti-inflammatory therapeutics should be investigated for the treatment of KCS.
12096226 Total costs and predictors of costs in individuals with early inflammatory polyarthritis: 2002 Jul OBJECTIVE: To estimate the health service, non-health service and total costs and predictors of costs in individuals with early inflammatory polyarthritis (IP). METHODS: We conducted a prospective longitudinal study over a 6-month period. The participants were a random sample of 133 individuals who had enrolled with the community-based Norfolk Arthritis Register (NOAR) database between 1994 and 1999. The main outcome measures were the mean (per person) 6-month health service cost, non-health-service cost and total cost associated with IP. RESULTS: One hundred and fifteen of the 133 individuals who were recruited into the study completed 6 months of follow-up. The mean 6-month total cost was estimated to be 2800 pounds sterling per person, of which 14% was health service costs and the remainder non-health-service costs. Higher total costs were associated with lower health status and rheumatoid factor positivity. CONCLUSIONS: Early IP has a considerable impact on both the health-care system and, more importantly, society. Non-health-service costs (i.e. costs incurred by the individual with the disease, their family and friends) account for a substantial proportion (86%) of the total costs associated with early IP.
12952500 Cannabis-based medicines--GW pharmaceuticals: high CBD, high THC, medicinal cannabis--GW p 2003 GW Pharmaceuticals is undertaking a major research programme in the UK to develop and market distinct cannabis-based prescription medicines [THC:CBD, High THC, High CBD] in a range of medical conditions. The cannabis for this programme is grown in a secret location in the UK. It is expected that the product will be marketed in the US in late 2003. GW's cannabis-based products include selected phytocannabinoids from cannabis plants, including D9 tetrahydrocannabinol (THC) and cannabidiol (CBD). The company is investigating their use in three delivery systems, including sublingual spray, sublingual tablet and inhaled (but not smoked) dosage forms. The technology is protected by patent applications. Four different formulations are currently being investigated, including High THC, THC:CBD (narrow ratio), THC:CBD (broad ratio) and High CBD. GW is also developing a specialist security technology that will be incorporated in all its drug delivery systems. This technology allows for the recording and remote monitoring of patient usage to prevent any potential abuse of its cannabis-based medicines. GW plans to enter into agreements with other companies following phase III development, to secure the best commercialisation terms for its cannabis-based medicines. In June 2003, GW announced that exclusive commercialisation rights for the drug in the UK had been licensed to Bayer AG. The drug will be marketed under the Sativex brand name. This agreement also provides Bayer with an option to expand their license to include the European Union and certain world markets. GW was granted a clinical trial exemption certificate by the Medicines Control Agency to conduct clinical studies with cannabis-based medicines in the UK. The exemption includes investigations in the relief of pain of neurological origin and defects of neurological function in the following indications: multiple sclerosis (MS), spinal cord injury, peripheral nerve injury, central nervous system damage, neuroinvasive cancer, dystonias, cerebral vascular accident and spina bifida, as well as for the relief of pain and inflammation in rheumatoid arthritis and also pain relief in brachial plexus injury. The UK Government stated that it would be willing to amend the Misuse of Drugs Act 1971 to permit the introduction of a cannabis-based medicine. GW stated in its 2002 Annual Report that it was currently conducting five phase III trials of its cannabis derivatives, including a double-blind, placebo-controlled trial with a sublingual spray containing High THC in more than 100 patients with cancer pain in the UK. Also included is a phase III trial of THC:CBD (narrow ratio) being conducted in patients with severe pain due to brachial plexus injury, as are two more phase III trials of THC:CBD (narrow ratio) targeting spasticity and bladder dysfunction in multiple sclerosis patients. Another phase III trial of THC:CBD (narrow ratio) in patients with spinal cord injury is also being conducted. Results from the trials are expected during 2003. Three additional trials are also in the early stages of planning. These trials include a phase I trial of THC:CBD (broad ratio) in patients with inflammatory bowel disease, a phase I trial of High CBD in patients with psychotic disorders such as schizophrenia, and a preclinical trial of High CBD in various CNS disorders (including epilepsy, stroke and head injury). GW Pharmaceuticals submitted an application for approval of cannabis-based medicines to UK regulatory authorities in March 2003. Originally GW hoped to market cannabis-based prescription medicines by 2004, but is now planning for a launch in the UK towards the end of 2003. Several trials for GW's cannabis derivatives have also been completed, including four randomised, double-blind, placebo-controlled phase III clinical trials conducted in the UK. The trials were initiated by GW in April 2002, to investigate the use of a sublingual spray containing THC:CBD (narrow ratio) in the following medical conditions: pain in spinal cord injury, pain and sleep in MS and spinal cord injury, neuropathic pain in MS and general neuropathic pain (presented as allodynia). Results from these trials show that THC:CBD (narrow ratio) caused statistically significant reductions in neuropathic pain in patients with MS and other conditions. In addition, improvements in other MS symptoms were observed as well. Phase II studies of THC:CBD (narrow ratio) have also been completed in patients with MS, spinal cord injury, neuropathic pain and a small number of patients with peripheral neuropathy secondary to diabetes mellitus or AIDS. A phase II trial of THC:CBD (broad ratio) has also been completed in a small number of patients with rheumatoid arthritis, as has a trial of High CBD in patients with neurogenic symptoms. A phase II trial has also been evaluated with High THC in small numbers of patients for the treatment of perioperative pain. The phase II trials provided positive results and confirmed an excellent safety profile for cannabis-based medicines. GW Pharmaceuticals received an IND approval to commence phase II clinical trials in Canada in patients with chronic pain, multiple sclerosis and spinal cord injury in 2002. Following meetings with the US FDA, Drug Enforcement Agency (DEA), the Office for National Drug Control Policy, and National Institute for Drug Abuse, GW was granted an import license from the DEA and has imported its first cannabis extracts into the US. Preclinical research with these extracts in the US is ongoing.