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ID PMID Title PublicationDate abstract
17272286 Cloning and expression of two human recombinant monoclonal Fab fragments specific for EBV 2007 Mar Serum titers of antibody to Epstein-Barr virus (EBV) viral capsid antigen (VCA) have been positively correlated with malignancies of lymphoid proliferation, such as Burkitt's lymphoma and Hodgkin's lymphoma. We have constructed a phage display combinatorial antibody Fab library from a patient with marginal zone B cell lymphoma associated with Sjögren's syndrome and carrying high serum anti-EBV-VCA IgG titer. Fab fragments were selected by panning against EBV-VCA protein coated onto ELISA plates, and selected Fab clones were characterized by ELISA, western blotting (WB), indirect immunofluorescence assay and immunohistochemistry. We have established two Fab clones, Fab-aVCA1 and Fab-aVCA21, which specifically recognize EBV-VCA by ELISA and WB. Inhibition ELISA competition showed that both clones could significantly reduce the binding of specific anti-EBV-VCA mAb to its relevant proteins. Furthermore, these two Fab clones could localize VCA protein in the EBV-positive P3HR1 and Daudi cell lines, as well as in tissue samples from patients with EBV-infected lymphoid malignancies. These results indicate that our two Fab clones are novel human mAbs specific for EBV-VCA protein and may have potential benefits for development of novel diagnostic and therapeutic approaches in EBV-related lymphoid malignancies.
18375405 Autoimmune reactivity against the 20S-proteasome includes immunosubunits LMP2 (beta1i), ME 2008 May OBJECTIVES: Autoantibodies against the 20S-proteasome display a broad diversity with a remarkably low frequency of individual cross-reactivity against the different subunits of the proteasome. Although their pathogenic and diagnostic significance remains obscure, an involvement in the clearance of circulating proteasomes as well as an interaction with the activity of the proteolytic complex was assumed in previous studies. METHODS: To investigate the anti-proteasome response in more detail and to disclose reactivities against former neglected subunits, two-dimensional electrophoresis followed by immunoblotting was used. As a novel antigen source, the immunosubunits LMP2 (beta1i) and LMP7 (beta5i) were expressed as recombinant proteins and employed in ELISA. RESULTS: The subunits Iota (alpha1) and Zeta (alpha5) of the outer rings as well as the catalytic subunit Delta (beta1) and all three immunosubunits [MECL-1 (beta2i), LMP2 (beta1i) and LMP7 (beta5i)] of the inner rings of the proteasome were identified as autoantigens for the first time. Using a panel of anti-proteasome antibody-positive sera of patients with SLE, autoimmune myositis (PM/DM) and primary Sjögren's syndrome (pSS), an autoimmune response was documented against LMP2 (beta1i) and LMP7 (beta5i) in all three patient groups in ELISA. CONCLUSIONS: The frequent autoimmune response against LMP2 (beta1i) and LMP7 (beta5i) might indicate a role of inflammatory processes in the primary induction of the anti-proteasomal immune reaction, while the diversity of the humoral response against the proteasome system supports the assumption of a specific antigen-driven process leading to these extended autoimmune reactivities.
17907141 Characterization of discriminant human brain antigenic targets in neuropsychiatric systemi 2007 Oct OBJECTIVE: To characterize discriminant human brain antigenic targets in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), using a standardized immunoproteomic approach. METHODS: Self-IgG reactivity against normal and injured human brain tissues was studied by Western blotting of sera from 169 subjects, 16 patients with NPSLE, 12 patients with SLE without neuropsychiatric manifestations (non-NPSLE), 32 patients with Sjögren's syndrome with or without central nervous involvement, 82 patients with multiple sclerosis, and 27 healthy subjects. A proteomic approach was then applied to characterize discriminant antigens identified after comparisons of all patterns. RESULTS: The serum self-IgG reactivity patterns against human brain tissue differed significantly between patients with NPSLE and the control groups. Four normal brain antigenic bands were specifically or preferentially recognized by sera from NPSLE patients (p240, p90, p77, and p24). Protein band p240 was characterized as microtubule-associated protein 2B (MAP-2B), p77 as Hsp70-71, and p24 as triosephosphate isomerase. Protein band p90 was not characterized. In contrast, 1 other protein band (p56, characterized as septin 7) was never recognized by sera from NPSLE patients but was recognized by a majority of sera from non-NPSLE patients. CONCLUSION: Our findings show that the immunoproteomic approach is a reliable method for assessing serum self-IgG reactivities against human brain tissue in NPSLE. Our characterization of some of the identified discriminant antigens, such as MAP-2B, triosephosphate isomerase, and septin 7, suggests that the stability of neuronal microtubules might be involved in the pathophysiology of NPSLE.
16806593 [Prevalence of Epstein-Barr virus in Sjögren's syndrome in Tunisia]. 2006 Jul PURPOSE: The cause of Sjögren's syndrome is unclear. Several studies suggested the role of Epstein-Barr virus (EBV) in the pathogenesis of this syndrome, but this always remains a subject of numerous controversies. The purpose of this study was to evaluate the prevalence of EBV in Sjögren's syndrome in Tunisia. METHODS: A series of 31 paraffin-embedded biopsies of salivary glands from patients with Sjögren's syndrome were studied in comparison with 19 control glands. EBV was investigated by PCR, EBERs in situ hybridization and by immunohistochemistry for the detection of LMP1, EBNA2 and ZEBRA. RESULTS: EBV DNA was detected by PCR in 3 of 22 PCR beta-globin positive Sjögren's syndrome cases (13.6%) and in 2 of 17 PCR beta-globin positive control glands (11.7%); in situ hybridization positivity was noted in rare lymphocytes in the 3 EBV positive cases of Sjögren's syndrome, but not in control glands; immunohistochemical study was negative in all cases. CONCLUSION: EBV infection does not appear to play a significant role in the pathogenesis of Sjögren's syndrome in Tunisia.
16702740 Long-term outcome of autoimmune pancreatitis after oral prednisolone therapy. 2006 OBJECTIVE: We investigated the long-term outcome of autoimmune pancreatitis (AIP) including morphological changes in the pancreas, pancreatic duct, biliary tract, pancreatic function, and changes in the clinical manifestations after oral prednisolone (PSL) therapy. PATIENTS AND METHODS: We prospectively followed 12 patients for a period of over 12 months (median follow-up period: 41 months; range: from 13 to 133 months). All twelve patients were treated with PSL. The morphological findings consisted of pancreatic enlargement (n=12), an irregularly narrowed main pancreatic duct (n=12), and bile duct stricture (n=10), and salivary gland swelling was observed in six patients. The initial dose of PSL was 30-40 mg/day, and it was subsequently tapered. RESULTS: All 12 patients responded to PSL therapy. The enlargement of the pancreas and the irregularly narrowed main pancreatic duct improved to almost normal. Pancreatic atrophy developed in four of them (4/12, 33%), but no pancreatic calcification was observed in any of the patients. The bile duct stricture improved to various degrees in all 10 patients , but it persisted in the lower part of the bile duct in four of them (4/10, 40%). The salivary gland swelling also improved after PSL therapy. There was no recurrence of enlargement of the pancreas or irregularly narrowed main pancreatic duct after PSL therapy, but the bile duct stricture recurred in one case, and in three cases there was a relapse of salivary gland swelling that required a temporary increase in PSL dose during tapering. No deterioration of pancreatic exocrine function was detected in any of the patients. A malignant tumor was diagnosed in two patients during PSL therapy: early gastric cancer in one and rectal cancer in the other. All patients are alive. CONCLUSIONS: AIP treated with PSL has a favorable long-term outcome based on the morphological findings and assessments of pancreatic function. However, since two of the twelve patients developed a malignancy during PSL therapy, strict follow up should be part of the management of AIP.
16414974 Immunoproteasome subunit LMP2 expression is deregulated in Sjogren's syndrome but not in o 2006 Aug BACKGROUND: The proteasome system has a pivotal role in the control of the immune response, which suggests that it might be involved in the pathogenesis of autoimmune disorders. OBJECTIVE: To investigate the expression profile of selected proteasomal genes in human peripheral blood mononuclear cells in patients with a variety of autoimmune diseases compared with healthy subjects. METHODS: Real time quantitative RT-PCR was used to analyse the mRNA expression pattern of the proteasome activator subunits PA28alpha and PA28beta and of constitutive proteasome and interferon-gamma-inducible immunoproteasome subunits in peripheral blood mononuclear cells. Simultaneously, protein expression of selected proteasome subunits was quantified by immunoblotting. RESULTS: Under systemic inflammatory conditions the proteasome subunits LMP2 (beta1i), LMP7 (beta5i), MECL1 (beta2i), and PA28alpha were expressed abundantly at the protein level in the vast majority of systemic autoimmune disorders. However, simultaneous mRNA and protein quantification showed a characteristic proteasome expression signature in primary Sjögren's syndrome. At the transcript level, the interferon-gamma-responsive subunits LMP2 (beta1i), MECL1 (beta2i), and the proteasome activator subunit PA28alpha were markedly up regulated. In contrast, LMP2 (beta1i) deficiency was evident at the protein level, indicating deregulation of proteasome expression in Sjögren's syndrome. CONCLUSIONS: These data provide evidence for a regulatory defect in the proteasome system in human autoimmune disorders, pointing to a unique role for LMP2 (beta1i) in the pathogenesis of primary Sjögren's syndrome.
18238768 Treatment of complications associated with systemic sclerosis. 2008 Feb 15 PURPOSE: Current and emerging drug therapy options for patients suffering from the complications of systemic sclerosis are presented. SUMMARY: Systemic sclerosis is a devastating and rare, chronic, autoimmune disease and is characterized by various disease complications due to skin thickening, vascular damage, and inflammation affecting numerous organs. There are two major subtypes of systemic sclerosis: limited cutaneous scleroderma and diffuse cutaneous scleroderma. Patients suffer from Raynaud's phenomenon, skin changes, musculoskeletal changes, gastrointestinal complications, pulmonary complications, scleroderma renal crisis, and dryness of the eyes and mouth. Currently, there is no cure for systemic sclerosis, but research is focusing on decreasing the progression and symptoms of this disease. Raynaud's phenomenon is the temporary vasoconstriction of the small vessels of the fingers, toes, tip of the nose, and earlobes. Skin thickening is the cardinal symptom of systemic sclerosis, with as many as 50% of patients developing digital ulcers. Care of these ulcers is crucial in the prevention of osteomyelitis and other infections. Malabsorption syndrome may also occur in patients, many of whom will eventually require parenteral nutrition to maintain their caloric needs. Pulmonary interstitial fibrosis and pulmonary arterial hypertension are additional serious complications of systemic sclerosis. The use of prostacyclin analogues, phosphodiesterase inhibitors, calcium-channel blockers, cyclophosphamide, bosentan, and other agents has been investigated in patients suffering from the complications of systemic sclerosis. CONCLUSION: Systemic sclerosis is characterized by various circulatory, dermatological, gastrointestinal, musculoskeletal, pulmonary, and renal complications. Although there is no cure for systemic sclerosis, management of its associated complications can help improve patients' quality of life.
18189193 Constitutive STAT3 activation in peripheral CD3(+) cells from patients with primary Sjögr 2008 Jan OBJECTIVE: Signal transducers and activators of transcription (STATs) are crucial mediators of cytokine signalling. Constitutive activation of STATs, especially STAT3, has been reported in several diseases. Primary Sjögren's syndrome (pSS) is associated with overproduction of cytokines such as interleukin-10 (IL-10), although the mechanism by which this occurs is unknown. As STAT3 is a potent inducer of IL-10, this study focused on determining the pattern of STAT3 activation in peripheral lymphocytes from patients with pSS. METHODS: Twelve pSS patients and 12 healthy age-matched control subjects were studied. Peripheral blood mononuclear cells (PBMCs) were isolated by gradient centrifugation. Phosphorylated STAT3 (pSTAT3) and also STAT3 expression were determined by flow cytometry in gated CD3(+ )and CD19(+) lymphocytes. Similarly, pJak1 and pTyk2 were also determined in gated CD3(+) lymphocytes. RESULTS: Although the protein expression of STAT3 was similar among controls and pSS patients, we found that STAT3 was constitutively activated in CD3(+) lymphocytes from pSS patients. Neither Jak1 nor Tyk2 (the upstream activators of STAT3) was activated in pSS CD3(+) lymphocytes, suggesting that the constitutive activation of STAT3 observed in pSS patients might not depend on cytokine stimulation but instead might be the result of an abnormal inactivation of pSTAT3. CONCLUSIONS: These data provide evidence of abnormal STAT3 signalling in T cells from pSS patients.
18085734 Renal involvement and followup of 130 patients with primary Sjögren's syndrome. 2008 Feb OBJECTIVE: To identify the clinical characteristics, pathological changes, and outcome of patients with primary Sjögren's syndrome (pSS). METHODS: All patients with pSS and renal involvement who were admitted to Ruijin Hospital from April 1993 to December 2006 were included. All the data of clinical features and pathological changes were retrospectively analyzed. Forty-one patients underwent renal biopsies. RESULTS Our study included 130 patients with pSS: 122 women and 8 men. Ages ranged from 16 to 68 years (mean 44.1 +/- 11.52). Ninety-five patients (73.1%) developed renal tubular acidosis (RTA); 91 were found to have distal RTA. Nine patients presented with hypokalemic paralysis. Four patients developed Fanconi syndrome and 3 were proved to have nephrogenic diabetes insipidus. Twenty-seven of 130 patients (20.8%) developed tubular proteinuria and 18/130 (13.8%) presented glomerular involvement. Thirty-five patients (27.7%) developed renal failure (serum creatinine > 115 micromol/l). Most patients (70.8%) had increased serum IgG levels. The incidence of chronic interstitial nephritis was 80.5% among all the biopsy materials. Immunofluorescent staining was negative in most renal tissue. Ninety-six patients were treated with corticosteroids and/or immunosuppressant. Eighteen recovered renal function. CONCLUSION: Patients with pSS commonly present with renal impairment, mainly from renal tubular dysfunction. The combination of corticosteroids and immunosuppressors significantly improves the renal function of patients with pSS. There is a correlation between hypergammaglobulinemia and distal RTA. The renal acidification capacity for patients with hypergammaglobulinemia. should be monitored.
17894006 Autoantibodies from Sjögren's syndrome trigger apoptosis in salivary gland cell line. 2007 Jun The presence of serum autoantibodies has been associated with Sjögren's syndrome (SS), an autoimmune rheumatic disease that targets salivary and lachrymal glands. The association of apoptosis with autoantibodies production seems to play a role in the pathogenesis of glandular damage. The best-defined antibodies in SS are those reacting with the ribonucleoprotein antigens SS-A (Ro) and SS-B (La). Anti-Ro antibodies are found in about 70-90%, and anti-La in approximately the same frequency, of patients with primary SS. The objective of this work was to explore whether anti-Ro and anti-La autoantibodies purified from Sjögren IgG fractions are able to trigger apoptotic process in the human salivary gland cell line A-253. Anti-Ro and anti-La autoantibodies were purified on protein G Sepharose affinity column and used for the A-253 cell treatment. Apoptosis induced by autoantibodies was revealed by FACS analysis, and the active caspase-3 and the cleaved caspase-3 substrate poly (ADP-ribose) polymerase (PARP) was demonstrated by colorimetric assay and Western blot. This report shows that anti-Ro and anti-La autoantibodies, but not healthy IgG, activate the caspase-3 and determine the cleavage of PARP in A-253 cells. Apoptosis triggered by Sjögren autoantibodies could be responsible for the impairment of the secretory function in the salivary glands.
16414973 Distinct recognition of antibodies to centromere proteins in primary Sjogren's syndrome co 2006 Aug BACKGROUND: Anticentromere antibodies are characteristically observed in scleroderma but have recently been reported in other autoimmune rheumatic disorders, including Sjögren's syndrome. It is not known whether distinct centromere proteins (CENP) are targeted in primary Sjögren's syndrome (pSS) and scleroderma. OBJECTIVE: To determine whether antibodies to CENP-B and CENP-C are present in these two disorders. METHODS: Sera from 45 patients with pSS and 33 with limited scleroderma were studied. All patients met classification criteria for pSS and scleroderma, respectively. Sera were used to immunoprecipitate in vitro translated CENP-B and CENP-C. The proportions recognising CENP-B or CENP-C were compared. RESULTS: 10 of 45 patients (22%) with pSS and 18 of 33 (55%) with scleroderma had antibodies recognising CENPs (p = 0.004). Seven of 10 (70%) CENP positive patients with pSS recognised CENP-C alone, compared with one of 18 (6%) CENP positive patients with scleroderma (odds ratio (OR) = 40 (95% confidence interval (CI), 3.5 to 450) (p = 0.003). In contrast, the majority (15 of 18 (83%)) of CENP positive scleroderma sera recognised both CENP-B and CENP-C, compared with none of 10 pSS sera (OR = 93 (95% CI, 4.4 to 1979) (p = 0.0001). CONCLUSIONS: The pattern of CENP recognition differs markedly in pSS and limited scleroderma. While patients with pSS predominantly recognise CENP-C alone, dual recognition of CENP-B and CENP-C is most frequent in scleroderma. These findings suggest that obtaining antibodies to specific centromere antigens is useful diagnostically, and imply that distinct mechanisms underlie the unique patterns of centromere autoreactivity in pSS and scleroderma.
18780535 The jaw functional limitation scale: development, reliability, and validity of 8-item and 2008 Summer AIMS: To develop the Jaw Functional Limitation Scale (JFLS), comprising 3 constructs and a global scale, based on a preliminary instrument, and to investigate content validity of the overall functional limitation construct, reliability, and generalizability. A temporomandibular disorders (TMD) patient group, compared to other diagnostic groups, was hypothesized to report further limitation in each of the 3 new proposed constructs. METHODS: One hundred thirty-two consecutive patients from 5 diagnostic groups (TMD, primary Sjogren syndrome, burning mouth syndrome, skeletal malocclusion, and healthy controls) participated in a known-groups validity design. Fifty-two jaw functional limitation items were identified by an expert panel for content validity. Rasch methodology was used for item reduction and assessment of model fit. The instrument was retested 1 to 2 weeks later. RESULTS: Three constructs (mastication, vertical jaw mobility, and emotional and verbal expression) comprising a total of 20 items were identified along with a global scale (the JFLS-20), and each exhibited excellent psychometric properties with respect to modeled variance, item fit, reliability, and internal consistency. The psychometric properties of each construct remained satisfactory when analyzed separately among the 5 diagnostic groups. Temporal stability was satisfactory. A shorter 8-item form (JFLS-8) also proved useful for assessing global functional jaw limitation. CONCLUSION: The JFLS-20 is an organ-specific instrument comprising 3 constructs for assessing functional status of the masticatory system; the 3 scales exhibit properties that are ideal for both research and patient evaluation in patient groups with a range of functional limitations of the jaw. The JFLS-8 emerged as a short form for measuring global functional limitation of the jaw.
17587445 Genetic variants of chemokine receptor CCR7 in patients with systemic lupus erythematosus, 2007 Jun 22 BACKGROUND: The chemokine receptor CCR7 is a key organizer of the immune system. Gene targeting in mice revealed that Ccr7-deficient animals are severely impaired in the induction of central and peripheral tolerance. Due to these defects, Ccr7-deficient mice spontaneously develop multi-organ autoimmunity showing symptoms similar to those observed in humans suffering from connective tissue autoimmune diseases. However, it is unknown whether mutations of CCR7 are linked to autoimmunity in humans. RESULTS: DNA samples were collected from 160 patients suffering from connective tissue autoimmune disease (Sjogren's syndrome, n = 40; systemic lupus erythematosus, SLE, n = 20 and systemic sclerosis, n = 100) and 40 health subjects (n = 40). All participants in this study were of German descent. Samples were screened for single nucleotide polymorphisms (SNP) by sequencing the coding region of the CCR7 gene as well asthe exon flaking intron sites and parts of the regions encoding for the 5'- and 3'-UTR. CCR7 variants were rare. We identified six different sequence variants, which occurred in heterozygosis. The identified SNP were observed at position -60 C/T (observed 1x), +6,476 A/G (7x), +6,555 C/T (15x), +6,560 C/T (6x), +10,440 A/G (3x) and +11,475 C/A (1x). Four of these variants (+6,476 A/G, +6,555 C/T, +6,560 C/T and +10,440 A/G) display allelic frequencies between 1% and 5 % and were present in both patients and control groups. The variants +6,476 A/G, +6,555 C/T, +6,560 C/T are located in the intron 2, while the +10,440 A/G variant corresponds to a silent mutation in exon 3. The variants -60 C/T and +11,475 C/A which are located at the 5'-UTR and 3-UTR respectively, display allelic frequencies below 1%. No correlation between these variants and the autoimmune diseases investigated could be observed. However, reporter gene expression assay demonstrated that the mutation at the -60 C/T position in homozygosis leads to reduced luciferase activity. CONCLUSION: These results suggest that variants of CCR7 gene occur at an extremely low frequency in the German population and that neither Sjogren's syndrome, systemic lupus erythematosus, nor systemic sclerosis are associated with these variants. Nevertheless, the decreased luciferase activity observed in cells transfected with the promoter region bearing the -60 C/T mutation suggests that this CCR7 variant could potentially lead to increased susceptibility to autoimmunity.
17379156 Salivary dysfunction associated with systemic diseases: systematic review and clinical man 2007 Mar OBJECTIVES: The objective of this study was to identify systemic diseases associated with hyposalivation and xerostomia and develop evidence-based management recommendations for hyposalivation/xerostomia. STUDY DESIGN: Literature searches covered the English language medical literature from 1966 to 2005. An evidence-based review process was applied to management studies published from 2002 to 2005. RESULTS: Several systemic diseases were identified. From studies published 2002 to 2005, 15 were identified as high-quality studies and were used to support management recommendations: pilocarpine and cevimeline are recommended for treating hyposalivation and xerostomia in primary and secondary Sjögren's syndrome (SS). IFN-alpha lozenges may enhance saliva flow in primary SS patients. Anti-TNF-alpha agents, such as infliximab or etanercept, are not recommended to treat hyposalivation in SS. Dehydroepiandrosterone is not recommended to relieve hyposalivation or xerostomia in primary SS. There was not enough evidence to support any recommendations for the use of local stimulants, lubricants, and protectants for hyposalivation/xerostomia. However, professional judgment and patient preferences may support the use of a specific product for an individual patient. CONCLUSIONS: These evidence-based management recommendations should guide the clinician's management decisions for patients with salivary dysfunction related to systemic disease. Future treatment strategies may include new formulations of existing drugs, e.g., local application of pilocarpine. Recent discoveries on gene expression and a better understanding of the etiopathogenesis of SS may open new treatment options in the future.
16537077 Distribution and roles of aquaporins in salivary glands. 2006 Aug Salivary glands are involved in secretion of saliva, which is known to participate in the protection and hydratation of mucosal structures within the oral cavity, oropharynx and oesophagus, the initiation of digestion, some antimicrobial defence, and the protection from chemical and mechanical stress. Saliva secretion is a watery fluid containing electrolytes and a mixture of proteins and can be stimulated by muscarinic and adrenergic agonists. Since water movement is involved in saliva secretion, the expression, localization and function of aquaporins (AQPs) have been studied in salivary glands. This review will focus on the expression, localization and functional roles of the AQPs identified in salivary glands. The presence of AQP1, AQP5 and AQP8 has been generally accepted by many, while the presence of AQP3, AQP4, AQP6 and AQP7 still remains controversial. Functionally, AQP5 seems to be the only AQP thus far to be clearly playing a major role in the salivary secretion process. Modifications in AQPs expression and/or distribution have been reported in xerostomic conditions.
18000691 The efficacy of Xialine in patients with Sjögren's syndrome: a single-blind, cross-over s 2008 Jun Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease of unknown cause whose main characteristic is severe dryness of the eyes and the mouth. The decreased functional capacity of the lacrimal and salivary glands which is the result of the inflammatory process and lymphocytic infiltration observed in SS is accountable for this complication. Twenty-nine patients with SS whose ages were ranging between 24-77, who were under treatment in Ege University Faculty of Medicine Department of Rheumatology, participated in the study, and their informed consents were obtained upon enrollment. Each patient recorded their subjective complaints on a separate questionnaire. The baseline and subsequent evaluation of the subjective findings on predetermined times (1 h after application of the material, at the end of the 1st, 7th, and 14th days) were also recorded on separate questionnaire sheets. Throughout the 14-day treatment period, no statistically significant differences were noted between the Xialine and placebo groups with regard to burning tongue, diminished taste, and waking up at night to sip water (p = 0.925, 0.527, and 0.066, respectively). However, patients' satisfaction with placebo decreased by 25.63% at the end of the test period, whereas it increased by 16.37% after Xialine administration. Overall, the patients preferred Xialine at the end of the study (p = 0.011). The main motive to administer saliva substitute is to improve lubrication and hydration of oral tissues. The results of this study indicated that Xialine is helpful in the management of xerostomia-related symptoms of SS patients. However, further investigations in larger scale group of patients are recommended to provide the effects of these agents on various complaints of xerostomia.
19166876 New advances in musculoskeletal pain. 2009 Apr Non-malignant musculoskeletal pain is the most common clinical symptom that causes patients to seek medical attention and is a major cause of disability in the world. Musculoskeletal pain can arise from a variety of common conditions including osteoarthritis, rheumatoid arthritis, osteoporosis, surgery, low back pain and bone fracture. A major problem in designing new therapies to treat musculoskeletal pain is that the underlying mechanisms driving musculoskeletal pain are not well understood. This lack of knowledge is largely due to the scarcity of animal models that closely mirror the human condition which would allow the development of a mechanistic understanding and novel therapies to treat this pain. To begin to develop a mechanism-based understanding of the factors involved in generating musculoskeletal pain, in this review we present recent advances in preclinical models of osteoarthritis, post-surgical pain and bone fracture pain. The models discussed appear to offer an attractive platform for understanding the factors that drive this pain and the preclinical screening of novel therapies to treat musculoskeletal pain. Developing both an understanding of the mechanisms that drive persistent musculoskeletal pain and novel mechanism-based therapies to treat these unique pain states would address a major unmet clinical need and have significant clinical, economic and societal benefits.
18768881 High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through bindi 2008 Sep 15 Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical to resolution of inflammation. Impaired efferocytosis is associated with an unfavorable outcome from inflammatory diseases, including acute lung injury and pulmonary manifestations of cystic fibrosis. High mobility group protein-1 (HMGB1), a nuclear nonhistone DNA-binding protein, has recently been found to be secreted by immune cells upon stimulation with LPS and cytokines. Plasma and tissue levels of HMGB1 are elevated for prolonged periods in chronic and acute inflammatory conditions, including sepsis, rheumatoid arthritis, acute lung injury, burns, and hemorrhage. In this study, we found that HMGB1 inhibits phagocytosis of apoptotic neutrophils by macrophages in vivo and in vitro. Phosphatidylserine (PS) is directly involved in the inhibition of phagocytosis by HMGB1, as blockade of HMGB1 by PS eliminates the effects of HMGB1 on efferocytosis. Confocal and fluorescence resonance energy transfer demonstrate that HMGB1 interacts with PS on the neutrophil surface. However, HMGB1 does not inhibit PS-independent phagocytosis of viable neutrophils. Bronchoalveolar lavage fluid from Scnn(+) mice, a murine model of cystic fibrosis lung disease which contains elevated concentrations of HMGB1, inhibits neutrophil efferocytosis. Anti-HMGB1 Abs reverse the inhibitory effect of Scnn(+) bronchoalveolar lavage on efferocytosis, showing that this effect is due to HMGB1. These findings demonstrate that HMGB1 can modulate phagocytosis of apoptotic neutrophils and suggest an alternative mechanism by which HMGB1 is involved in enhancing inflammatory responses.
20443835 Effect of the soluble TNF-antagonist etanercept on tumor necrosis factor bioactivity and s 2008 Sep BACKGROUND: Targeted anti-tumor necrosis factor (TNF) strategies in patients with rheumatoid arthritis have resulted in new and/or worsening heart failure in individuals who were free of cardiovascular disease. METHODS AND RESULTS: To determine the mechanism of new and/or worsening heart failure in patients who were receiving the soluble TNF-antagonist etanercept, we analyzed frozen plasma samples from a previous clinical trial with etanercept in heart failure patients, and conducted complimentary mechanistic in vitro studies. Analysis of the clinical trial data showed that use of etanercept resulted in a significant 70-fold increase in the level of immunoreactive TNF. Complimentary in vitro studies using an L929 bioassay showed that at low concentrations of etanercept relative to TNF there was an unexpected 1.5- to 1.75-fold increase in the absolute level of TNF bioactivity. We also examined the effect of etanercept on TNF stability and the results showed that there was a two-fold increase in the mass of bioactive homotrimeric TNF when the molar ratio of TNF to etanercept was approximately 200:1. CONCLUSION: Etanercept increases the immunoreactive mass of TNF in heart failure patients, as well as augments TNF cytotoxicity in certain settings, thus suggesting one potential mechanism for the worsening heart failure in some patients who were receiving this agent.
17585219 Bulleyaconitine A isolated from aconitum plant displays long-acting local anesthetic prope 2007 Jul BACKGROUND: Bulleyaconitine A (BLA) is an active ingredient of Aconitum bulleyanum plants. BLA has been approved for the treatment of chronic pain and rheumatoid arthritis in China, but its underlying mechanism remains unclear. METHODS: The authors examined (1) the effects of BLA on neuronal voltage-gated Na channels in vitro under the whole cell patch clamp configuration and (2) the sensory and motor functions of rat sciatic nerve after single BLA injections in vivo. RESULTS: BLA at 10 microm did not affect neuronal Na currents in clonal GH3 cells when stimulated infrequently to +50 mV. When stimulated at 2 Hz for 1,000 pulses (+50 mV for 4 ms), BLA reduced the peak Na currents by more than 90%. This use-dependent reduction of Na currents by BLA reversed little after washing. Single injections of BLA (0.2 ml at 0.375 mm) into the rat sciatic notch not only blocked sensory and motor functions of the sciatic nerve but also induced hyperexcitability, followed by sedation, arrhythmia, and respiratory distress. When BLA at 0.375 mm was coinjected with 2% lidocaine (approximately 80 mm) or epinephrine (1:100,000) to reduce drug absorption by the bloodstream, the sensory and motor functions of the sciatic nerve remained fully blocked for approximately 4 h and regressed completely after approximately 7 h, with minimal systemic effects. CONCLUSIONS: BLA reduces neuronal Na currents strongly at +50 mV in a use-dependent manner. When coinjected with lidocaine or epinephrine, BLA elicits prolonged block of both motor and sensory functions in rats with minimal adverse effects.