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ID PMID Title PublicationDate abstract
17094336 [Tuberculosis in rheumatic patients treated with tumour necrosis factor alpha antagonists: 2006 Jul In Portugal, 13 cases of tuberculosis (TB) were reported, in the period between 1999 and 2005, in 960 patients exposed to anti-TNFalpha treatment (1.35%), 8 females and 5 males. Mean age was 46.7 +/- 13.8 years. 9 patients had rheumatoid arthritis (RA), in 639 exposed patients (1.4%), 3 had ankylosing spondylitis (AS), in 200 exposed patients (1.5%) and 1 had psoriatic arthritis (PA), in 101 exposed patients (1%). The anti-TNFa used was in 8 cases infliximab (in 456 patients exposed, 1.5%), in 4 adalimumab (in 171 patients exposed, 2.3%) and in 1 etanercept (in 333 exposed, 0.3%). Treatment with a biological agent was started 11.1 +/- 8.7 months (min 3 and max 50) before TB onset. Tuberculin skin test (TST) was performed in 9 out of the 13 patients (the other 4 had started biological therapy before 2002). In 3 cases the TST response was 0 mm, in 3 less than 10 mm, in one was 14 mm and in two 20 mm. In the 3 cases with a TST response superior to 10 mm, isoniazid treatment 300 mg/d was prescribed, during 9 months. The time between first symptoms and TB diagnosis was 2.6 +/- 2.9 months. TB involvement was pulmonary in 6 patients, lymph node disease in 2, peritoneal and pulmonary in 2, osteoarticular in one case, lymph node disease and splenic in another and miliar TB in the last case. One death was reported; all of the other cases had a good outcome after anti-TB treatment. In two cases (one treated with adalimumab and the other with infliximab), paradoxical response to treatment occurred. None of the patients has restarted biological therapy after TB treatment.
16533508 Effect of glutamate receptor antagonists and antirheumatic drugs on proliferation of synov 2006 Mar 27 One of the most striking features of inflammatory arthritis is the hyperplasia of synovial fibroblasts. It is not known whether the massive synovial hyperplasia characteristic of rheumatoid arthritis is due to the proliferation of synovial fibroblasts or to defective apoptosis. It has been found that glutamate receptor antagonists inhibit proliferation of different human tumour cells and the anticancer potential of glutamate receptor antagonists was suggested. Here, we investigated the effect of glutamate receptor antagonists and selected antirheumatic drugs on proliferation of synoviocytes in vitro. Experiments were conducted on rabbit synoviocytes cell line HIG-82 obtained from American Type Culture Collection (Menassas, VA, USA). Cell proliferation was assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 value (the concentration of drug necessary to induce 50% inhibition) together with confidence limits was calculated. Glutamate receptor antagonists, 1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one (CFM-2), riluzole, memantine, 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), dizocilpine, ketamine and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), inhibited proliferation of synoviocytes with the following IC50 values (in mM): 0.014, 0.017, 0.065, 0.102, 0.15, 0.435 and 1.16, respectively. Antirheumatic drugs, celecoxib, diclofenac, nimesulide, sulfasalazine, naproxen and methotrexate, inhibited proliferation of synoviocytes with the following IC50 values (in mM): 0.0043, 0.034, 0.044, 0.096, 0.385 and 1.123, respectively. Thus, the antiproliferative potential of glutamate receptor antagonists is comparable to that of antirheumatic drugs.
15719322 Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collec 2005 Apr Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these disorders. Until very recently, no specific alleles--aside from a few common human leukocyte antigen class II genes--had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). At least two of nine "core" autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease (Crohn disease or ulcerative colitis), psoriasis, and primary Sjogren syndrome. We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes.
16698665 Identification of nuclear spliceosomal antigens targeted by NOD mouse antibodies following 2006 Mar The non-obese diabetic (NOD) mouse spontaneously develops a range of autoreactive responses including an autoantibody response to nuclear antigens. As elevated dietary iodine has been shown to increase thyroid autoimmune pathology in NOD mice, the effect of sodium iodide (NaI) on the development of anti-nuclear antibodies (ANA) was assessed. Interestingly, the NaI symporter is expressed in both thyroid and salivary glands. Elevated dietary iodine was found to increase the percentage of male NOD mice developing autoantibodies. Specifically, the nuclear autoantibodies that develop in NOD mice were shown to target specific spliceosomal components. The target specificity of the autoantibodies was determined using recombinant spliceosomal proteins and shown to include U1A, U170K, U2B'', U2A', as well as the Sm proteins D1, D2, and B. The autoantibody isotypes most consistently represented were IgG2a and IgG2b.
16255767 Antimitochondrial antibodies in patients with chronic hepatitis C virus infection: descrip 2005 Nov To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton-fixed criosections and FITC-conjugated rabbit anti-human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjögren's syndrome (n = 7), systemic sclerosis (n = 3) and systemic lupus erythematosus (n = 2). Fourteen (78%) of the HCV-AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia (n = 4), cirrhotic complications (n = 2) and hepatopulmonary syndrome (n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated SAD, mainly Sjögren's syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia.
16234186 Adult heart block is associated with disease activity in primary Sjögren's syndrome. 2005 Sep OBJECTIVES: Congenital heart block occurring in the foetus and neonate may be associated with maternal anti-SS-A/anti-SS-B autoantibodies (anti-SSA/anti-SSB). The adult atrioventricular node is generally thought to be resistant to the damaging effects of anti-SSA/anti-SSB. However, case reports suggest that heart block developing in adult Sjögren's syndrome (SS) patients may be associated with these autoantibodies. Therefore, we investigated the relationship between serum antibodies and heart block in adult SS patients. METHODS: We abstracted data from clinic patient records. Diagnosis of primary SS was based on American-European classification criteria. Electrocardiograms (EKGs), laboratory immunology parameters, lipid profiles, and focus scores from labial salivary gland biopsies were available for 51 SS patients. Fifteen patients had follow-up EKGs. PR interval200 ms was considered to be first-degree heart block. RESULTS: Five patients showed prolonged PR intervals; the presence of heart block was not related to the presence of anti-SSA antibodies. However, significant differences between patients with prolonged and normal PR intervals were seen for mean focus scores (p<0.0001), anti-cardiolipin immunoglobulin IgG (p = 0.0009), age (p = 0.01), IgG (p = 0.02), anti-SSB antibodies (p = 0.02), and high density lipoprotein (HDL) cholesterol levels (p = 0.03). These parameters correlated with prolonged PR intervals. CONCLUSIONS: These results suggest an association between disease activity, the presence of anti-SSB antibodies, and the occurrence of first-degree heart block in adults with primary SS.
16331857 TNF blockade: an inflammatory issue. 2006 Tumor necrosis factor (TNF), initially discovered as a result of its antitumor activity, has now been shown to mediate tumor initiation, promotion, and metastasis. In addition, dysregulation of TNF has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis, Crohn's disease, multiple sclerosis, psoriasis, scleroderma, atopic dermatitis, systemic lupus erythematosus, type II diabetes, atherosclerosis, myocardial infarction, osteoporosis, and autoimmune deficiency disease. TNF, however, is a critical component of effective immune surveillance and is required for proper proliferation and function of NK cells, T cells, B cells, macrophages, and dendritic cells. TNF activity can be blocked, either by using antibodies (Remicade and Humira) or soluble TNF receptor (Enbrel), for the symptoms of arthritis and Crohn's disease to be alleviated, but at the same time, such treatment increases the risk of infections, certain type of cancers, and cardiotoxicity. Thus blockers of TNF that are safe and yet efficacious are urgently needed. Some evidence suggests that while the transmembrane form of TNF has beneficial effects, soluble TNF mediates toxicity. In most cells, TNF mediates its effects through activation of caspases, NF-kappaB, AP-1, c-jun N-terminal kinase, p38 MAPK, and p44/p42 MAPK. Agents that can differentially regulate TNF expression or TNF signaling can be pharmacologically safe and effective therapeutics. Our laboratory has identified numerous such agents from natural sources. These are discussed further in detail.
16026123 [Selective cyclooxygenase-2 inhibitors. A population-based analysis of use in France over 2005 Jun 4 OBJECTIVES: The use of selective cyclooxygenase-2 (COX-2) inhibitors is highly controversial today, mainly because of doubts about cardiovascular tolerance. Few studies have assessed the use of these drugs in daily clinical practice. This study aims to assess the changes in their use in daily practice in France and to compare it with their use in randomized clinical trials. METHODS: The French National Health Insurance Fund AMPI database of self-employed workers in non-agricultural occupations was used to obtain the following information: patients requesting reimbursement for celecoxib and rofecoxib between November 2000 and October 2003, morbidity assessed by enrollment on the lists of chronic diseases for which care is fully (100%) reimbursed, pregnancy (assessed by the payment of physicians' or hospital fees for delivery or by maternity benefits), and concomitant drugs (by claims for reimbursement). We compared these patients with those in randomized clinical trials (RCT) of celecoxib or rofecoxib published in either English or French before November 2003; we focused on their demographic characteristics, morbidity, pregnancy and concomitant drug use. RESULTS: Use of COX-2 inhibitors in France did not vary over the study period, except for patients' mean age (range: 64.2-62.9 years), proportion of women (56.7%-54.7%) and use of gastroprotective drugs (18.2%-28.4%). The mean age of patients in our study was 10 years older than that of RCT patients, and the proportion of women in our study was 15% lower. The percentage of women who took these drugs while pregnant was 0.02% in our study and 0.09% in the RCT. The percentage of patients with long-term chronic disorders overall was higher in our study than in the RCT, and the percentage for all specific long-term diseases except rheumatoid arthritis was also higher (for example, more patients had cardiovascular diseases or diabetes in our study [15%] than in the RCT [6%]). Patients in our study also used concomitant drugs from 9 of the 14 principal Anatomical Therapeutic Chemical classification groups more frequently than RCT patients: for cardiovascular drugs, for example, the figures were 55% and 5%, respectively. CONCLUSION: The demographic characteristics, prevalence of chronic morbidity and use of concomitant drugs among COX-2 inhibitor users in France varied little over the three years after marketing approval. Compared with RCT patients, these users were less often female, were older and more often had cardiovascular diseases. Cardiovascular events occurring among COX-2 inhibitor users in France should be evaluated.
17081464 [Influence of preoperative range of motion on the early clinical outcome of total knee art 2006 Aug 15 OBJECTIVE: To retrospectively analyze the influence of preoperative range of motion (ROM) and maximal flexion degree on the early clinical outcome of total knee arthroplasty (TKA). METHODS: From January 2000 to December 2003, 97 knees of 65 patients that were underwent total knee arthroplasty with Scorpio posterior-stabilized knee prosthesis were reviewed. There were 55 osteoarthritis patients (81 knees), and 10 rheumatoid arthritis (16 knees). Thirty-three patients were underwent unilateral TKA, 32 patients were underwent bilateral TKA. According to the preoperative ROM of knee, these patients were divided into two groups, one 90 degrees (range, 95 degrees - 140 degrees ). Finally the clinical outcomes of two groups (include ROM, maximal flexion degree, KSS score and function score) were evaluated. Three days later after operation, continuous passive motion (CPM) and active functional exercise of the knee were begun, and the wound healed well in all patients. All these operations were primary total knee arthroplasty. RESULTS: The patients were followed up for average 2 years 5 months (range, 10 months to 3 years 8 months). The average ROM of knee was improved to 101.6 degrees (range, 40 degrees - 140 degrees ) after operation from 84.2 degrees (range, 5 degrees - 140 degrees ) before operation (P = 0.000); the average maximal flexion degree was decreased from 103.5 degrees (range, 25 degrees - 140 degrees ) before operation to 101.6 degrees (range, 40 degrees - 140 degrees ) after operation (P = 0.439); KSS of knee joint was improved to 78.8 points after operation (range, 50 - 95 points) from 19.5 points (-24 - 62 points) before operation (P = 0.000). There was statistically difference between the clinical outcomes (ROM, maximal flexion degree, KSS score and function score) in the two groups before and after operation. Those knees with good preoperative ROM tend to lose flexion, while those with poor preoperative ROM gain flexion after TKA. No revision and deep infection happened. CONCLUSIONS: TKA is a complex operation, the clinical outcome of TKA is mainly determined by the good operation skill, abundant clinical experience and the familiarity with the prosthesis of the surgeon. At the same conditions such as same surgeon, same prosthesis and same physical therapy, preoperative range of motion of knee influence on the early clinical outcome of total knee arthroplasty, knees that have good preoperative ROM have better clinical outcomes postoperatively than those with poor preoperative ROM.
16879746 Characterisation of the immune response to type I collagen in scleroderma. 2006 This study was conducted to examine the frequency, phenotype, and functional profile of T lymphocytes that proliferate in response to type I collagen (CI) in patients with scleroderma (SSc). Peripheral blood mononuclear cells (PBMCs) from SSc patients, healthy controls, and rheumatoid arthritis disease controls were labeled with carboxy-fluorescein diacetate, succinimidyl ester (CFSE), cultured with or without antigen (bovine CI) for 14 days, and analysed by flow cytometry. Surface markers of proliferating cells were identified by multi-color flow cytometry. T-cell lines were derived after sorting for proliferating T cells (CFSElow). Cytokine expression in CI-responsive T cells was detected by intracellular staining/flow cytometry and by multiplex cytokine bead assay (Bio-Plex). A T-cell proliferative response to CI was detected in 8 of 25 (32%) SSc patients, but was infrequent in healthy or disease controls (3.6%; p = 0.009). The proliferating T cells expressed a CD4+, activated (CD25+), memory (CD45RO+) phenotype. Proliferation to CI did not correlate with disease duration or extent of skin involvement. T-cell lines were generated using in vitro CI stimulation to study the functional profile of these cells. Following activation of CI-reactive T cells, we detected intracellular interferon (IFN)-gamma but not interleukin (IL)-4 by flow cytometry. Supernatants from the T-cell lines generated in vitro contained IL-2, IFN-gamma, GM-CSF (granulocyte macrophage-colony-stimulating factor), and tumour necrosis factor-alpha, but little or no IL-4 and IL-10, suggesting that CI-responsive T cells express a predominantly Th1 cytokine pattern. In conclusion, circulating memory CD4 T cells that proliferate to CI are present in a subset of patients with SSc, but are infrequent in healthy or disease controls.
17261796 Estrogens and autoimmune diseases. 2006 Nov Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors . Several physiological, pathological, and therapeutic conditions may change the serum estrogen milieu and/or peripheral conversion rate, including the menstrual cycle, pregnancy, postpartum period, menopause, being elderly, chronic stress, altered circadian rhythms, inflammatory cytokines, and use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. In particular, cortisol and melatonin circadian rhythms are altered, at least in rheumatoid arthritis (RA), and partially involve sex hormone circadian synthesis and levels as well. Abnormal regulation of aromatase activity (i.e., increased activity) by inflammatory cytokine production (i.e., TNF-alpha, IL-1, and IL-6) may partially explain the abnormalities of peripheral estrogen synthesis in RA (i.e., increased availability of 17-beta estradiol and possible metabolites in synovial fluids) and in systemic lupus erythematosus, as well as the altered serum sex-hormone levels and ratio (i.e., decreased androgens and DHEAS). In the synovial fluids of RA patients, the increased estrogen concentration is observed in both sexes and is more specifically characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, which is a mitogenic and cell proliferative endogenous hormone. Local effects of sex hormones in autoimmune rheumatic diseases seems to consist mainly in modulation of cell proliferation and cytokine production (i.e., TNF-alpha, Il-1, IL-12). In this respect, it is interesting that male patients with RA seem to profit more from anti-TNFalpha strategies than do female patients.
16968406 Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppre 2006 Oct Macrophages/monocytes and the proinflammatory mediators, such as tumour necrosis factor (TNF)-alpha, prostaglandin E(2) (PGE(2)), macrophage inflammatory protein (MIP)-1alpha and MIP-1alpha, play a critical role in the progression of immunological disorders including rheumatoid arthritis, Behçet's disease and Crohn's disease. In addition, the nicotinic acetylcholine receptor-alpha7 (alpha7nAChR) subunit is an essential regulator of inflammation. In this study, we evaluated the expression of the alpha7nAChR subunit on human peripheral monocytes and the effect of nicotine on the production of these proinflammatory mediators by activated monocytes. Fluorescein isothiocyanate (FITC)-labelled alpha-bungarotoxin demonstrated the cell surface expression of the alpha7nAchR subunit. Pretreatment with low-dose nicotine caused inhibition of TNF-alpha, PGE(2), MIP-1alpha and MIP-1alpha production, and mRNA expression of TNF-alpha, MIP-1alpha and MIP-1alpha and COX-2 in lipopolysaccharide (LPS)-activated monocytes. These suppressive effects of nicotine were caused at the transcriptional level and were mediated through alpha7nAChR. Nicotine suppressed the phosphorylation of I-kappaB, and then inhibited the transcriptional activity of nuclear factor-kappaB. These immunosuppressive effects of nicotine may contribute to the regulation of some immune diseases.
16958136 Inhibitors of CXCR4 affect the migration and fate of CXCR4+ progenitors in the developing 2006 Nov Chemokines and their receptors play major roles in numerous physiological and pathological processes during development and disease. CXCR4 is the most abundantly expressed chemokine receptor during development. In contrast to other chemokine receptors, CXCR4 binds and is activated exclusively by its ligand stromal derived factor-1 (SDF-1) or CXCL12. SDF-1 signaling has a wide range of effects on CXCR4-expressing cells depending on the cell type ranging from cell growth to adhesion, chemotaxis, and migration. CXCR4 also serves as a co-receptor for HIV-1 entry into T-cells and has been implicated in the pathogenesis of rheumatoid arthritis and cancer growth and invasion. Numerous inhibitors and antagonists of CXCR4 have been produced and are being tested for their efficiency to target its role in pathogenesis. Our initial expression analysis revealed that CXCR4 is expressed by the migrating myogenic and angiogenic precursors in the developing chick limb. In this study, we used the most specific peptidic inhibitors of CXCR4, T140 and its analog TN14003, to analyse the effect of blocking CXCR4/SDF-1 signaling on the undetermined bioptent migratory progenitors in the developing chick limb. Our results point to defects in migration and an altered differentiation program of these CXCR4-expressing progenitor pool in the limb.
16799886 Oral dimethyl sulfoxide for systemic amyloid A amyloidosis complication in chronic inflamm 2006 May BACKGROUND: Amyloid A amyloidosis is an obstinate disease complication in chronic inflammatory disease, and there are few effective therapies. The objective of this study was to investigate the effect of oral dimethyl sulfoxide (DMSO) on amyloid A amyloidosis. METHODS: Fifteen secondary amyloid A amyloidosis patients (4 men, 11 women; age, 23-70 years) were treated with DMSO between 1995 and 2003. DMSO was administered orally in all patients at a dose of 3-20 g/day. The clinical symptoms together with the renal and gastrointestinal functions were evaluated before and after treatment. RESULTS: Among the 15 patients, amyloid A amyloidosis was a complication of rheumatoid arthritis (RA) in 10, of Crohn's disease in 4, and of Adult Still's disease in 1. Nine cases mainly involved the kidney, with renal dysfunction and proteinuria, five mainly involved the gastrointestinal tract, with protein-losing gastroenteropathy and intractable diarrhea, and one involved both gastrointestinal and renal amyloidosis. DMSO treatment was successful in 10 (66.7%) of the 15 patients (RA, 6/10; Crohn's disease, 4/4; Adult Still's disease, 0/1). Eight weeks of DMSO administration improved the renal function and proteinuria in five out of ten renal amyloidosis patients, but had no effect on those patients with severe and/or advanced renal dysfunction. With regard to gastrointestinal amyloidosis, gastrointestinal symptoms, including diarrhea and protein-losing gastroenteropathy, were improved in six patients. No serious side effects were encountered with the DMSO treatment. CONCLUSIONS: Oral administration of DMSO is an effective treatment for amyloid A amyloidosis, especially for gastrointestinal involvement and the early stage of renal dysfunction.
16717269 Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. 2006 May 23 BACKGROUND: Chronic noncancer pain (CNCP) is a major health problem, for which opioids provide one treatment option. However, evidence is needed about side effects, efficacy, and risk of misuse or addiction. METHODS: This meta-analysis was carried out with these objectives: to compare the efficacy of opioids for CNCP with other drugs and placebo; to identify types of CNCP that respond better to opioids; and to determine the most common side effects of opioids. We searched MEDLINE, EMBASE, CENTRAL (up to May 2005) and reference lists for randomized controlled trials of any opioid administered by oral or transdermal routes or rectal suppositories for CNCP (defined as pain for longer than 6 mo). Extracted outcomes included pain, function or side effects. Methodological quality was assessed with the Jadad instrument; analyses were conducted with Revman 4.2.7. RESULTS: Included were 41 randomized trials involving 6019 patients: 80% of the patients had nociceptive pain (osteoarthritis, rheumatoid arthritis or back pain); 12%, neuropathic pain (postherpetic neuralgia, diabetic neuropathy or phantom limb pain); 7%, fibromyalgia; and 1%, mixed pain. The methodological quality of 87% of the studies was high. The opioids studied were classified as weak (tramadol, propoxyphene, codeine) or strong (morphine, oxycodone). Average duration of treatment was 5 (range 1-16) weeks. Dropout rates averaged 33% in the opioid groups and 38% in the placebo groups. Opioids were more effective than placebo for both pain and functional outcomes in patients with nociceptive or neuropathic pain or fibromyalgia. Strong, but not weak, opioids were significantly superior to naproxen and nortriptyline, and only for pain relief. Among the side effects of opioids, only constipation and nausea were clinically and statistically significant. INTERPRETATION: Weak and strong opioids outperformed placebo for pain and function in all types of CNCP. Other drugs produced better functional outcomes than opioids, whereas for pain relief they were outperformed only by strong opioids. Despite the relative shortness of the trials, more than one-third of the participants abandoned treatment.
16674108 Activity-based matrix metallo-protease enrichment using automated, inhibitor affinity extr 2006 May An automated inhibitor affinity extraction method for the activity-based enrichment of matrix metallo-proteases (MMPs) is presented. Samples containing purified MMP-12 were first extracted at different flow rates in a syringe pump setup, using cartridges packed with an MMP inhibitor affinity sorbent based on an immobilized hydroxamic acid containing peptide (PLG-NHOH) with mumol/L MMP affinity. Faster extractions, a reduced number of manual manipulations, and higher extraction yields (98.9%-99.3%) were obtained over the whole flow rate range compared to batch extractions. Application of the method to synovial fluid from a rheumatoid arthritis patient followed by gelatin-zymography revealed a strong enrichment of distinct MMPs from this biological sample that were not clearly visible in the original sample. The use of an auto-sampler and a solid-phase extraction (SPE) workstation allowed full automation of the extraction procedure with the potential for on-line coupling to further sample preparation and analytical steps. MMP-12 extractions were optimized showing that ligand density is an important factor with a clear extraction yield optimum around 5 to 7.5 mmol/L. Conditioning of the stationary phase for 1 week prior to use resulted in a further slight increase in extraction yield. Under optimal conditions, an extraction yield of 99.5% was reached with a cartridge contact time of only 13 s for MMP-12. The efficacy of the extraction method for activity-based MMP profiling was further improved by the use of a broad-spectrum MMP inhibitor with nmol/L affinity (TAPI-2). This resulted in an increased extraction yield for all tested MMPs. For MMP-1, -7, -8, -10, -12, and -13 extraction yields of at least 98.8% were obtained, while for MMP-9 (full length and catalytic domain) an extraction yield of at least 96.1% was reached.
16514653 Effect of wrist and ulna head position on gliding resistance of the extensor digitorum min 2006 Apr While attrition from sharp bony surfaces is the most common cause of extensor digiti minimi (EDM) tendon rupture, the etiology of other cases of spontaneous EDM tendon rupture is still unknown. Friction within the compartment may play a role, especially with ulna dislocation. The purpose of this study was to compare gliding resistance of the EDM tendon with that of a tendon which rarely ruptures spontaneously, the extensor digitorum communis of the middle finger (EDC III) tendon, under various wrist and ulna head positions. Eight fresh frozen cadavers were used. Gliding resistance between the tendon and its sheath in each compartment was measured in five different wrist positions and three different ulna head positions. Gliding resistance of the EDM tendon (0.13 +/- 0.03 N) was significantly greater than the EDC III tendon (0.09 +/- 0.03 N) (p < 0.05). For the EDM tendon, the gliding resistance in ulnar deviation or pronation was higher than the gliding resistance in neutral, radial deviation, or supination (p < 0.05), and the gliding resistance with ulnar lengthening (over 6 mm) or dorsal ulnar dislocation (over 9 mm) was higher than in neutral ulnar head positioning. For the EDC III tendon, the gliding resistance in ulnar deviation was significantly higher than the gliding resistance in neutral, radial deviation, or supination, or dorsal dislocation with ulnar lengthening (p < 0.05). Wrist ulnar deviation, ulnar dorsal dislocation (over 9 mm), and ulnar lengthening (over 6 mm) increased the gliding resistance of the EDM tendon. In patients at risk for EDM rupture, such as those with rheumatoid arthritis or distal radioulnar joint osteoarthritis, avoiding such positions may be advantageous.
16489323 Omega 3 fatty acids: biological activity and effects on human health. 2005 Dec Polyunsaturated fatty acids (PUFAs) have an important role in human diet, both for the prevention and the therapy of different pathologies. In this review, a critical evaluation of PUFAs dietary sources and biological functions in human organism has been done. In particular, the efficacy of omega-3 fatty acids in the improvement of the lipidic pattern and in the excitability of myocardium has been analyzed, and, therefore, their usefulness in the prevention of cardiovascular diseases and postinfarction arrhythmias. As PUFAs are precursors of prostaglandins and leucotriens, which are involved in phlogosis and immune response, a diet rich in fish oil reduces the production of PGE2 involved in many phlogosis events. Moreover, an increase in the eicosapentaenoic acid (EPA) intake leads to a reduction in the production of inflammatory cytokines (interleukin 1, 2, 6 and tumor necrosis factor); so, it is important to use omega-3 in chronic inflammatory diseases, as the rheumatoid arthritis. It seems that omega-3 could prevent the onset of hormone-dependent tumours (i.e. breast and prostatic cancer); in vitro observations, in fact, have shown that the PG of the series 2, derived from omega-6, have a carcinogenic action; instead, the anticancer effect of omega-3 could derive from their effect in antagonizing the formation of such PG; it can be useful, therefore, to increase the dietary omega-3/omega-6 ratio. Moreover, the effects of omega-3 on the anatomic and functional central nervous system development and of their possible therapeutical use in some psychiatric pathologies were evaluated.
16467190 Celecoxib inhibits interleukin-12 alphabeta and beta2 folding and secretion by a novel COX 2006 May Celecoxib (CE) is a nonsteroidal anti-inflammatory drug (NSAID) that is a specific inhibitor of cyclooxygenase 2 (COX2). It is indicated for a variety of chronic inflammatory conditions, including rheumatoid arthritis. Over the last few years, adverse cardiovascular effects and increased risk for heart attacks have been associated with this drug. In addition, evidence is emerging for COX2-independent molecular targets. CE has been shown to induce apoptosis in various cancer cells lines through a COX2-independent mechanism that seems to involve inactivation of protein kinase Akt and inhibition of endoplasmic reticulum (ER) Ca2+ ATPase. In this study, we show that both CE and an analog devoid of COX2 inhibitory activity [1-(4-sulfamoyl phenyl)-3-trifluoromethyl-5-(4-trifluoromethylphenyl)pyrazole, CEA] inhibit the secretion of the dimeric interleukin-12 (IL-12) alphabeta and beta2 forms with identical IC50 values of 20 and 30 microM, respectively, whereas no such effect was seen with rofecoxib. Reverse transcription-polymerase chain reaction analysis showed that this inhibition was not due to a blockage of transcription of the alpha- and beta-chain expression cassettes. Secretion of the beta monomer form was less strongly inhibited, suggestive for a mechanism primarily targeting dimer assembly in the ER. Analysis of intracellular fractions revealed that both CE and CEA increased the association of IL-12 with calreticulin, an endoplasmic reticulum-resident chaperone involved in the retention of misfolded cargo proteins while blocking interaction with ERp44. Our findings reveal a previously undescribed effect of celecoxib on oligomer protein folding and assembly in the endoplasmic reticulum and ensuing secretion and suggest that celecoxib-driven alteration of the secretome may be involved in some of its clinical side effects.
16439062 Remnant epitopes, autoimmunity and glycosylation. 2006 Apr The role of extracellular proteolysis in innate and adaptive immunity and the interplay between cytokines, chemokines and proteinases are gradually becoming recognized as critical factors in autoimmune processes. Many of the involved proteinases, including those of the plasminogen activator and matrix metalloproteinase cascades, and also several cytokines and chemokines, are glycoproteins. The stability, interactions with inhibitors or receptors, and activities of these molecules are fine-controlled by glycosylation. We studied gelatinase B or matrix metalloproteinase-9 (MMP-9) as a glycosylated enzyme involved in autoimmunity. In the joints of rheumatoid arthritis patients, CXC chemokines, such as interleukin-8/CXCL8, recruit and activate neutrophils to secrete prestored neutrophil collagenase/MMP-8 and gelatinase B/MMP-9. Gelatinase B potentiates interleukin-8 at least tenfold and thus enhances neutrophil and lymphocyte influxes to the joints. When cartilage collagen type II is cleaved at a unique site by one of several collagenases (MMP-1, MMP-8 or MMP-13), it becomes a substrate of gelatinase B. Human gelatinase B cleaves the resulting two large collagen fragments into at least 33 peptides of which two have been shown to be immunodominant, i.e., to elicit activation and proliferation of autoimmune T cells. One of these two remnant epitopes contains a glycan which is important for its immunoreactivity. In addition to the role of gelatinase B as a regulator in adaptive immune processes, we have also demonstrated that it destroys interferon-beta, a typical innate immunity effector molecule and therapeutic cytokine in multiple sclerosis. Furthermore, glycosylated interferon-beta, expressed in Chinese hamster ovary cells, was more resistant to this proteolysis than recombinant interferon-beta from bacteria. These data not only prove that glycosylation of proteins is mechanistically important in the pathogenesis of autoimmune diseases, but also show that targeting of glycosylated proteinases or the use of glycosylated cytokines seems also critical for the treatment of autoimmune diseases.