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ID PMID Title PublicationDate abstract
7554442 Differential regulation of human T lymphocyte protein kinase C activity by unsaturated fat 1995 Sep Administration of gamma-linolenic acid suppresses active synovitis in patients with rheumatoid arthritis. We therefore examined the effects of gamma-linolenic acid and its first metabolite, dihomo-gamma-linolenic acid, on protein kinase C, a key element in transduction of signals from cell surface to nucleus. We report here that gamma-linolenic acid and dihomo-gamma-linolenic acid suppress total protein kinase C activity, but facilitate translocation of protein kinase C activity from cytosol to membrane in human peripheral blood T lymphocytes stimulated with phorbol 12-myristate 13-acetate. Arachidonic acid and eicosapentaenoic acid do not influence total protein kinase C activity and have only modest effects on enzyme translocation. These findings in whole cells are in contrast to results of experiments performed with isolated protein kinase C, in which unsaturated fatty acids uniformly enhance protein kinase C activity. The differential effects of unsaturated fatty acids underscore the complexity of protein kinase C regulation and indicate that gamma-linolenic and dihomo-gamma-linolenic acids influence T lymphocyte protein kinase C metabolism in a manner that is unique among unsaturated fatty acid precursors of eicosanoids.
7532674 Antifibrillarin autoantibodies present in systemic sclerosis and other connective tissue d 1995 Mar 1 Autoantibodies specific against fibrillarin, a 34-kD nucleolar protein associated with U3-snRNP, are present in patients with systemic sclerosis (SSc). To understand the mechanisms involved in the induction of these autoantibodies, we prepared a series of human fibrillarin recombinant proteins covering the entire molecule and analyzed their interaction with the autoantibodies present in various connective tissue diseases. Our results showed that antifibrillarin autoantibodies are present not only in SSc, as previously reported, but also in a variety of other connective tissue diseases. Patients with SSc (58%), mixed connective tissue diseases (60%), CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dismotility, sclerodactyly, and telangiectasia syndrome) (58%), systemic lupus erythematosus (39%), rheumatoid arthritis (60%), and Sjogern's syndrome (84%) showed presence of antifibrillarin autoantibodies. Results obtained from competitive inhibition radioimmunoassay and Western blot analyses with purified recombinant fusion proteins revealed that these autoantibodies react primarily with epitope(s) present in the NH2- (AA 1-80) and COOH-terminal (AA 276-321) domains of fibrillarin. Autoantibodies reacting with internal regions of fibrillarin are less frequent. Analysis of the hydrophilicity profiles of reactive peptides showed presence of three potential antigenic sites in the NH2- and two in the COOH-terminal regions. While a hexapeptide sequence NH2 terminus of fibrillarin is shared with an Epstein-Barr virus-encoded nuclear antigen, the COOH-terminal region shares sequence homology with P40, the capsid protein encoded by herpes virus type 1. Interestingly, these two regions of fibrillarin also contain the most immunodominant sequences, as predicted by surface probability and the Jameson and Wolf antigenic index. These observations suggest that molecular mimicry might play an important role in the induction of antifibrillarin autoantibodies.
7828374 Anti-microfilament IgG antibodies in normal adults and in patients with autoimmune disease 1995 Feb We have investigated IgG antibodies to microfilament-associated proteins in sera from 29 normal controls and from 172 patients with autoimmune diseases such as rheumatoid arthritis (n = 45), systemic lupus erythematosus (n = 43), polymyositis/dermatomyositis (n = 36), systemic sclerosis (n = 35), and autoimmune chronic active hepatitis (CAH, n = 13). We observed, by indirect immunofluorescence, a staining pattern in which the fluorescence was continuously distributed along microfilaments by using several animal and human cell lines as substrate. Because no reactivity with individual bands or specific combinations of bands was observed by immunoblotting using different cell lines, we further characterized our sera by immunoblotting using a panel of the purified microfilament-associated proteins filamin, myosin, alpha-actinin, actin, tropomyosin, and myosin light chain. Results shows that normal as well as autoimmune sera are polyreactive with microfilament proteins. The specificity of reactivity against a particular microfilament-associated protein was demonstrated by inhibition experiments with the specific protein. No correlation was observed between immunoblot and immunofluorescence results. Of the 201 sera, 40 (20%), 42 (21%), 31 (15%), 26 (13%), 34 (17%), 24 (12%), 4 (2%), and 0 (0%) reacted, respectively, by immunoblotting with 0, 1, 2, 3, 4, 5, 6, or 7 of the microfilament-associated proteins. Furthermore, 57 different profiles of reactivity with the panel proteins were observed. All autoimmune CAH sera reacted with at least 3 proteins. This result was strikingly unique to this group. Anti-actin antibodies were as common in normal as in CAH sera. Anti-alpha-actinin antibodies were strikingly more frequent in CAH than in any group. We conclude that a remarkable diversity of anti-microfilament antibodies is present in normal as well as in autoimmune sera and that a continuous microfilament fluorescent pattern is not restricted simply to anti-actin antibodies. Furthermore, sera negative by immunofluorescence react with several miocrofilament-associated proteins by immunoblotting. Reactivity with multiple (> or = 3) microfilament-associated proteins including alpha-actinin distinguishes CAH sera from normal and other autoimmune sera.
7657477 The use of n-3 PUFAs (fish oil) in enteral nutrition. 1995 Severely ill patients in need of enteral nutrition support must obtain all essential nutrients in at least the amounts recommended for daily intake (RDA) by healthy populations. Until recently essential fatty acids have been entirely omitted from enteral solutions or included only in the form of n-6 PUFAs which are structurally important for cell membranes and play a significant role as precursors (esp. arachidonic acid, AA) of eicosanoids (prostaglandins, thromboxanes, leukotrienes). However, in the absence of n-3 PUFAs, these eicosanoids may produce exaggerated effects in acute stress responses causing immunosuppression, platelet aggregation and excessive or chronic inflammation. n-3 PUFAs act as precursors of complementary eicosanoids which counteract the exaggerated responses of AA-derived eicosanoids. Therefore, n-3 PUFAs should be part of any optimally balanced diet and must be included also in enteral solutions. Since the transformation of the n-3 parent fatty acid, alpha-linolenic acid, to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is slow and unreliable, it is necessary to provide them as preformed nutrients as they occur in fish oil. The British Nutrition Foundation recommends a daily intake of EPA and DHA in amounts corresponding to the intake of 3 to 4 g standardized fish oil. The requirements can also be covered by the weekly consumption of 2 to 3 portions of fatty fish. Preliminary clinical trials have shown certain beneficial effects of fish oil intakes in diseases associated with inflammatory reactions such as rheumatoid arthritis or inflammatory bowel disease, in conditions with impaired immune competence such as burns, post-operative situations and cyclosporine treatment after renal transplants, and in conditions with enhanced platelet aggregation such as after coronary angioplasty. While these findings must be verified in strictly controlled trials, the intake of fish oil n-3 PUFAs in a balanced ratio to n-6 PUFAs can be recommended for all patients including those in need of enteral nutrition support.
7837145 Clinical course of cognitive dysfunction in systemic lupus erythematosus. 1994 Oct OBJECTIVE: To prospectively evaluate changes in cognitive function in a cohort of unselected patients with systemic lupus erythematosus (SLE) and controls over a 12 month period. METHODS: Seventy female patients with SLE, 25 patients with rheumatoid arthritis (RA) and 23 healthy subjects (age and sex matched) were evaluated using the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Wechsler Memory Scale-Revised (WMS-R), the California Verbal Learning Test (CVLT) and the National Adult Reading Test-Revised to identify impairment in 8 areas of cognitive function. Cumulative disease manifestations and current medications were documented, and disease activity was expressed using the SLE disease activity index (SLEDAI). Decision rules were determined for overall cognitive impairment. RESULTS: At baseline, 21% (15/70) of patients with SLE were impaired compared to 4% (1/25) of patients with RA and 4% (1/23) of healthy subjects (p = 0.042). After a mean interval of 12.8 months (range: 11-17) 84% (59/70) of patients with SLE, 44% (11/25) of patients with RA and 80% (17/23) of healthy subjects were reassessed. This included all subjects who were impaired at the initial assessment. Using the same decision rules as at baseline, 12% (7/59) of patients with SLE were impaired at followup compared to none of the patients with RA and healthy subjects. Over the period of study cognitive impairment persisted in 3 patients with SLE, resolved in 12 and evolved in 4 others. There was no apparent association between changes in cognitive function and concurrent changes in generalized disease activity, overt neuropsychiatric disease or corticosteroid medication. CONCLUSION: Our results suggest that cognitive dysfunction in patients with SLE is evanescent, does not necessarily lead to irreversible neurologic compromise and changes independently of other clinical variables.
8063757 Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition 1994 Aug 19 Monocytes/macrophages are associated with chronic inflammatory lesions, such as periodontal disease and rheumatoid arthritis, in which there is extensive connective tissue destruction. Stimulation of human monocytes results in the production of matrix metalloproteinases (MMPs) via a prostaglandin E2 (PGE2)-cAMP-dependent pathway. Modulation of many monocyte functions by interleukin 10 (IL-10) suggested that this cytokine may influence the signal transduction pathway leading to the production of MMPs by monocytes. Pre-incubation of monocytes with IL-10 for 1 h prior to stimulation with ConA resulted in significant inhibition of prostaglandin H synthase-2 (PGHS-2, the inducible form of prostaglandin synthase). In contrast, PGHS-1, the constitutive PGHS, was not affected by IL-10. Suppression of PGHS-2 mRNA and protein levels was detected at 1 ng/ml of IL-10 with maximal inhibition at 20 ng/ml. Nuclear run-on transcription assays performed on monocytes exposed to ConA or the combination of ConA and IL-10 indicated that IL-10 treatment suppressed PGHS-2 expression at the level of transcription. Attenuation of PGHS-2 by IL-10 was accompanied by decreased prostaglandin production, including PGE2. The decrease in prostaglandin production was primarily related to the effect of IL-10 on PGHS-2, since the release of arachidonic acid was unaffected by this cytokine. The inhibition of PGE2 production by IL-10 resulted in the suppression of mRNA and protein for interstitial collagenase and 92-kDa type IV collagenase/gelatinase (gelatinase B). This conclusion is supported by the ability of exogenously added PGE2 or dibutyryl cAMP to restore the production of MMPs in IL-10-treated monocytes. Additionally, PGHS-2 was also restored by PGE2 or dibutyryl cAMP, indicating that PGHS-2 is regulated through a PGE2-cAMP amplification pathway. These data add further support to the anti-inflammatory properties of IL-10.
7983645 Heterogeneity of the anti-Ro(SSA) response in rheumatic diseases. 1994 Aug OBJECTIVE: The immune response to the Ro(SSA) antigen is heterogeneous. Anti-Ro(SSA) positive sera may contain antibodies recognizing either a 60 or a 52 kDa polypeptide component of the Ro(SSA) particle. Thus we sought to determine the profile of anti-Ro(SSA) antibodies defined by immunoblotting in patients with rheumatic diseases. METHODS: Immunoblotting against human placenta extract and ELISA against recombinant Ro(SSA) antigen as confirmatory tests were done to detect anti-Ro(SSA) antibodies in 563 sera from patients with systemic lupus erythematosus (SLE). Sjögren's syndrome (SS), rheumatoid arthritis (RA) and other connective tissue diseases. RESULTS: Anti-52 kDa antibodies were more common in primary patients with SS (9/22; 40.9%) than in patients with SLE (29/135; 21.4%) or patients with RA (7/315; 2.2%). Anti-60 kDa antibodies were more frequent in patients with SLE (26/135; 19.2%) than in patients with primary SS (2/22; 9%) or RA (17/315; 5.3%). None of the 22 patients with primary SS had only antibodies to the 60 kDa polypeptide. Among the 153 patients whose sera were positive by ELISA, 73 (47.7%) were negative by immunoblotting. The most frequent diagnoses in these sera were RA and SLE. The anti-52 kDa sera had higher optical density values compared to anti-60 kDa sera. CONCLUSIONS: Our observations indicate the existence of qualitatively and quantitatively different anti-Ro(SSA) responses in the rheumatic diseases. The major responses are anti-52 kDa antibodies in primary SS, both anti-52 and anti-60 kDa antibodies in SLE, and anti-60 kDa antibodies in RA and other connective tissue diseases.
8038709 The interleukin-1 receptor antagonist and its delivery by gene transfer. 1994 Spring The interleukin-1 receptor antagonist (IL-1ra or IRAP) is a small, acidic glycoprotein that competitively inhibits the biological activities of interleukin-1 (IL-1). Alternative splicing gives rise to secreted and intracellular forms of IL-1ra. Both forms block cellular responses to IL-1 by occupying IL-1 receptors without triggering an agonist response. The affinity of IL-1ra for the type I IL-1 receptor is approximately that of IL-1. However, because of IL-1's pronounced "spare receptor" effect, IL-1ra is a weak inhibitor of biological responses to IL-1. The value for the affinity constant of IL-1ra's binding to the type II IL-1 receptor has been the subject of disagreement. However, recent data suggest that human IL-1ra has only weak affinity for the human type II receptor. This is consistent with the likelihood that the type II receptor plays no role in signal transduction, instead being a "decoy" that can be shed as a soluble receptor with the ability bind, and thus inhibit, IL-1. Under the name Antril, IL-1ra is being tested in clinical trials of a number of human diseases where IL-1 plays a major pathophysiologic role. These diseases include sepsis, rheumatoid arthritis, chronic myelogenous leukemia, and asthma, among others. Although IL-1ra has clear pharmacologic potential in such conditions, its application in chronic diseases is limited by difficulties associated with delivering proteins as drugs. As an alternative, we have suggested transfer of the gene coding for IL-1ra; strategies for both local and systemic gene delivery are being developed.(ABSTRACT TRUNCATED AT 250 WORDS)
8370929 Characterization of monoclonal antibodies specific for the V beta 3 family of the human T 1993 Sep 15 A soluble, recombinant form of the human T cell receptor (TCR) beta-chain containing the V beta 3.1 sequence has been constructed, expressed in Chinese hamster ovary cells, amplified by dihydrofolate reductase selection, and purified in quantities appropriate for the generation of monoclonal antibodies (mAb). The V beta 3 sequence was chosen because of its reported elevated usage in the synovial T cells of rheumatoid arthritis patients but the approach described should be applicable to other known human V beta gene sequences. By this method, two mAb were prepared which reacted with up to 10% of normal, live peripheral blood T cells but with reactivity varying greatly among individual donors. Both mAb specifically bound to a murine T cell line transfected with a human TCR V beta 3.1 and immunoprecipitated a protein of the expected molecular weight for the TCR beta-chain. Both antibodies were mitogenic for T cells and analysis of peripheral blood lymphocyte cultures stimulated with the mAb suggested that both were specific for the V beta 3.1 subfamily and not D beta or J beta. Clones expressing V beta 3, which were derived from mAb-stimulated peripheral blood lymphocytes of a single individual, preferentially (8/13), but not exclusively, utilized the J beta 2.7 gene segment. The V beta 3.1 usage showed no preference for the CD8+ or CD4+ subpopulations of normal peripheral blood T cells.
8407091 Preliminary, dermatologic first step criteria for lupus erythematosus and second step crit 1993 Sep BACKGROUND: Comparisons of cases of systemic lupus erythematosus (SLE) with cases of rheumatoid arthritis and other rheumatologic disorders affords the basis of the 1982 revised criteria of the American Rheumatism Association (ARA) for classifying SLE cases. We address three questions: Do comparisons of LE cases with non-LE cases that have suggestive skin lesions yield criteria for use in dermatology clinics for primary classification of cases with photo distributions of skin lesions? Do comparisons of SLE with cutaneous LE cases yield the same or similar criteria to the revised ARA criteria for SLE? How should subacute cutaneous LE cases be evaluated for signs of significant systemic involvement? METHODS: Discriminant analyses on 168 cases with skin lesions suggestive of LE were performed using data based on the ARA criteria for SLE and study factors for cutaneous LE suggested by the European Academy of Dermatology and Venereology. RESULTS: These yielded two sets of criteria: (1) The 11 preliminary, dermatologic first step criteria (10 plus 1 for discoid lesions and histology) serve to classify cases as LE or non-LE. (2) The 11 preliminary, dermatologic second step criteria classify LE cases as cutaneous LE or systemic LE. Interestingly, 5 of 11 of these second step criteria differ from the 11 ARA criteria for systemic LE. These second step criteria afford a useful means of distinguishing between subacute cutaneous LE cases with or without significant systemic involvement. CONCLUSIONS: The study factors included in both the first and the second step criteria fall into three groups, notably clinical criteria, laboratory criteria, and "added study factors." The latter factors distinguish between the groups compared (LE vs. non-LE and cutaneous vs. systemic LE) but not as well as the study factors included as "criteria."
7802875 Utilization of upper limb joint replacements during 1972-90: the Mayo Clinic experience. 1993 Increasing application of expensive medical technologies, including joint replacement, is of concern in the current economic climate. Successful upper limb joint replacements (ULJRs) are being performed, but few detailed data about their utilization are available. To explore the resource implications of such surgery, the utilization of total shoulder replacement (TSR), total elbow replacement (TER) and total wrist replacement (TWR) were examined from the time these procedures first became available at the Mayo Clinic up to 1990. The age- and sex-adjusted utilization rate for TSR among Olmsted County, Minnesota, residents was 1.8 per 100,000 person-years (p-y), 0.8 per 100,000 p-y for TER and 1.1 per 100,000 p-y for TWR. Overall utilization of primary ULJR among Olmsted County residents during the 19-year study period was 3.8 per 100,000 p-y. The commonest indication for TSR was osteoarthritis (46 per cent) and for TER and TWR was rheumatoid arthritis (50 and 81 per cent respectively). There was no consistent trend in the utilization of these procedures among Olmsted County residents, but the number of referral patients receiving a ULJR at the Mayo Clinic increased steadily during the study period. The Mayo Clinic experience suggests an increasing demand for ULJR, particularly TSR and TER. With continued advances in, and diffusion of, the technology this demand may increase further.
1466365 Antineutrophil cytoplasmic antibodies: a still-growing class of autoantibodies in inflamma 1992 Dec Antineutrophil cytoplasmic antibodies (ANCA) have been described as sensitive and specific markers for active Wegener's granulomatosis (WG). ANCA in WG produce a characteristic cytoplasmic staining pattern of neutrophils (c-ANCA) and are directed against proteinase 3 (Pr3), a serine protease from the azurophilic granules. c-ANCA, more or less equivalent to anti-Pr3, occur in more than 90% of patients with extended WG, in 75% of patients with limited WG without renal involvement, and in some 40% to 50% of patients with vasculitic overlap syndromes suggestive of WG such as microscopic polyarteritis. The presence of c-ANCA is highly specific for those diseases (greater than 98%). Changes of levels of c-ANCA precede disease activity and may be used as guidelines for treatment. Antibodies producing a perinuclear staining of ethanol-fixed neutrophils (p-ANCA) occur in a wide range of diseases. They are directed against different cytoplasmic constituents of neutrophils. Among those, antibodies to myeloperoxidase are found in patients with idiopathic crescentic glomerulonephritis, the Churg-Strauss syndrome, polyarteritis nodosa with visceral involvement, and vasculitic overlap syndromes. Their specificity for this group of necrotizing vasculitides is high (94% to 99%), although they may occur in patients with hydralazine-induced glomerulonephritis, anti-glomerular basement membrane disease, and possibly in some patients with idiopathic systemic lupus erythematosus. Antibodies to leukocyte elastase are incidentally found in patients with vasculitic disorders, whereas lactoferrin antibodies are detected in patients with primary sclerosing cholangitis with or without ulcerative colitis and in rheumatoid arthritis. Their diagnostic significance awaits further studies. p-ANCA of undefined specificity may distinguish ulcerative colitis (sensitivity of 75%) from Crohn's disease (sensitivity of 20%). p-ANCA also occur in autoimmune liver diseases: in 75% of patients with chronic active hepatitis, in 60% to 85% of those with primary sclerosing cholangitis, and in about 30% of patients with primary biliary cirrhosis. Finally, p-ANCA are detected in chronic arthritides and in some 5% of healthy controls. Assessment of their diagnostic value has to await further characterization of the antigens involved, allowing the development of antigen-specific assays.
1476008 [Determination of regional rate of glucose metabolism in lumbar muscles in patients with g 1992 Sep Generalized tendomyopathy (GTM), or fibromyalgia (FM), is a disease characterized by wide-spread pain in the musculoskeletal system which usually begins at a single site, e.g., as low-back pain or cervical syndrome, and develops into generalized pain over months or years. The disorder affects primarily women, beginning around the age of 35 and reaching its peak during or after the menopause. Its etiology is still unknown. Secondary forms are observed particularly in rheumatoid arthritis. In order to get more information on FM we determined the local metabolic rate of glucose in vivo in the skeletal muscle (lumbar region) with dynamic 18F-FDG positron emission tomography (PET). 2 healthy volunteers and 6 female patients with FM reaching in age from 31 to 53 years were scanned. As 18F-FDG PET scanning is a metabolic tool, it is crucial to observe standardized conditions of metabolic steady-state. We used, therefore, the hyperinsulinemic euglycemic insulin clamp technique to stimulate the myogenic glucose uptake under stable plasma-glucose levels. The local metabolic rates of glucose utilization were estimated with a non-linear least squares fit on the 3 compartment 18F-FDG-model. A lumped constant of 0.67 was assumed. Under glucose clamp conditions patients with FM showed a significantly (p < 0.001) lower metabolic rate of glucose (4.3 +/- 1.1) mumol/100 g tissue/min compared with normal volunteers (8.5 +/- 2.3 mumol/100 g/min). Due to a significantly (p < 0.005) increased glucose backflow from tissue into the vascular space (k2 in the kinetic model) the rate of phosphorylation was markedly reduced in patients with FM.(ABSTRACT TRUNCATED AT 250 WORDS)
1310711 A murine CD4-, CD8- T cell receptor-gamma delta T lymphocyte clone specific for herpes sim 1992 Feb 15 The role of TCR-gamma delta T lymphocytes in immune responses is currently not well understood. TCR-gamma delta cells have a limited repertoire suggesting that TCR-gamma delta T a limited number of evolutionarily conserved Ag such as nonpolymorphic MHC and heat shock proteins. TCR-gamma delta T lymphocytes appear in enhanced numbers in skin lesions produced by Mycobacterium leprae and in the synovial fluid of joints affected by rheumatoid arthritis, raising the possibility that this subset of T lymphocytes may play a role in control of infectious processes and in autoimmune diseases. We report the identification of a TCR-gamma delta T cell clone isolated from a HSV-infected mouse that recognizes glycoprotein I of HSV type 1. Clone recognition of glycoprotein I does not appear to require the expression of MHC class I or class II gene products. These data suggest that TCR-gamma delta lymphocytes may play an important role in the immune response to viral infections.
1738126 Biochemical and pharmacological activities of SR 26831, a potent and selective elastase in 1992 Feb SR 26831 ([[5-(2-chloro-benzyl-2-(terbutyloxycarbonyl)]-4,5,6,7- tetrahydrothieno(3,2-c)pyridine]N-oxide) is the first member of a new class of human leukocyte elastase inhibitors. SR 26831 inhibited in a dose-dependent manner elastases from human leukocytes or pancreas with IC50 values of 80 +/- 2.6 nM and 4.8 +/- 0.12 microM, respectively. Steady-state studies revealed that SR 26831 behaved like a noncompetitive, irreversible inhibitor of both types of enzymes. SR 26831 inhibited in a dose-dependent manner degradation of [3H]elastin and [3H]collagens (types I and IV) by human leukocyte elastase (IC50 values were between 1.2 and 1.8 microM). In this respect, SR 26831 was 3- to 20-fold more active than alpha-1-antitrypsin. SR 26831 was also highly selective for elastases inasmuch as it did not inhibit pepsin, collagenase, trypsin, alpha-chymotrypsin, factor Xa, plasmin, kallikrein, cathepsins B, C, D and G and thrombin. In the rabbit, SR 26831 was cleared rapidly from blood after i.v. injection, but affected intracellular leukocyte elastase activity shortly after either i.v. or p.o. administration. In the rat, i.v. or p.o. administration of SR 26831 prevented in a dose-dependent manner acute lung injury induced by intratracheal instillation of human leukocyte elastase. SR 26831 (1 mg/kg) was still efficient when it was administered 90 min before elastase instillation and was also able to limit further hemorrhage development in response to elastase, after it had begun. SR 26831 may therefore be of therapeutic value in the treatment of diseases such as rheumatoid arthritis or pulmonary emphysema thought to be due to the destructive action of leukocyte elastase.
1639152 Effect of aging and caloric restriction on intestinal permeability. 1992 Intestinal permeability is increased in several disorders such as Crohn's disease or rheumatoid arthritis. Since aging leads to alteration of many biological functions, the effect of aging on intestinal permeability was studied by measuring the intestinal permeability in aging rats gavaged with different size permeability probes--mannitol, polyethylene glycol (PEG) 400, and inulin. In rats fed with control diet, there was a significant increase in intestinal permeability to medium size probes PEG 400 (14.8 +/- 0.4 and 21.0 +/- 1.1% at 3 and 28 months respectively, p less than .01) and mannitol (3.41 +/- 0.4 and 5.3 +/- 0.5% at 3 and 28 months, respectively, p less than .01). Intestinal permeability of the large macromolecule inulin did not change (0.42 +/- 0.03 and 0.38 +/- 0.02% at 3 and 28 months, respectively) with aging. There was no correlation between weight of the rats and their intestinal permeability. Because dietary caloric restriction has been found to prolong the life span, retard deterioration of several biological functions, and affect intestinal absorptive functions, we examined the effect of lifelong calorie restriction on intestinal permeability changes. Lifelong calorie-restricted diet did not affect age-related change in intestinal permeability. We conclude that intestinal permeability of medium size probes increases with aging and that lifelong caloric restriction does not prevent this change. We speculate that age-associated deterioration in intestinal barrier functions could permit increased systemic absorption of lumenal antigens and could perhaps contribute to the genesis of antigen-related age-associated diseases.
8943302 Novel group V phospholipase A2 involved in arachidonic acid mobilization in murine P388D1 1996 Dec 13 Four related genes encode four different secretory phospholipase A2 (sPLA2) enzymes in mammals, namely the well described Group I and IIA enzymes and the more recently described Groups IIC and V. A large body of research has putatively demonstrated that the Group IIA sPLA2 is involved in diverse pathologic processes, such as rheumatoid arthritis, septic shock, intestinal neoplasia, and epidermal hyperplasia, as well as in cellular signaling by regulating the formation of arachidonate-derived lipid messengers. However, we demonstrate herein the involvement of another sPLA2, i.e. the Group V sPLA2, in arachidonic acid release and prostaglandin production in the mouse macrophage-like cell line P388D1. Abundant message for Group V sPLA2 was detected in both resting and activated cells. In contrast, Group IIA sPLA2 message was undetectable as analyzed by Northern blot and reverse transcriptase-polymerase chain reaction. Moreover, blockage of Group V sPLA2 gene expression by antisense RNA oligonucleotides resulted in inhibition of prostaglandin E2 production as well as reduction of the amount of sPLA2 protein at the cellular surface. Collectively, these results uncover Group V sPLA2 as a novel effector involved in arachidonic acid-mediated signal transduction.
8584484 Pharmacokinetic studies of methotrexate in plasma and synovial fluid following i.v. bolus 1995 Oct PURPOSE: The pharmacokinetic properties of methotrexate (MTX) in the plasma and synovial fluid (SF) after bolus i.v. and topical administration were studied in dogs to assess the feasibility of topical delivery of MTX for the treatment of rheumatoid arthritis. METHODS: A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. RESULTS: Peak MTX concentrations in SF occurred at 38 +/- 5 min following bolus i.v. dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 +/- 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 +/- 1.2 hr) and SF (12.7 +/- 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 +/- 0.21 hr) was longer than that in plasma (2.56 +/- 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at approximately 4 hr, lasting for approximately 20 hr. The bioavailability of MTX from the gel was 11.8 +/- 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. CONCLUSIONS: Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.
7659095 Anti-DNA and anti-platelet specificities of SLE-derived autoantibodies: evidence for CDR2H 1995 Jul Although polyreactivity appears to be a characteristic feature of natural autoantibodies, polyreactive anti-DNA autoantibodies can be derived both from patients with autoimmune disease and from normal individuals. It is unclear whether these autoantibodies differ depending on their origin, but previous studies from our laboratory have suggested that polyreactive systemic lupus erythematosus (SLE)-derived platelet-binding anti-DNA autoantibodies have more restricted antigen reactivity and greater functional activity than normal-derived polyreactive autoantibodies. The objective of the present study was to characterize the VH and VL region sequences of 10 human hybridoma anti-DNA autoantibodies derived from peripheral blood lymphocytes of different origins [SLE, rheumatoid arthritis (RA), or normal] to determine whether there are structural differences between these autoantibodies. We show that although some unmutated germline structures (VH and VL) are represented, these are not restricted to anti-DNA autoantibodies from normal individuals and that two normal-derived anti-DNA antibodies showed quite extensively mutated VH genes. However, these mutations, unlike those found in the CDR2H of several of the SLE-derived antibodies, did not appear to be antigen-selected. Three different amino acid motifs, putatively involved in antigen binding specificity, were observed in the CDR3H segments of some of the autoantibodies. One was the previously described YYGSG motif, which was found in a normal-derived anti-DNA autoantibody, while two new potential motifs were observed only in SLE-derived platelet-binding anti-DNA autoantibodies. These data suggest that antigenic and functional differences between SLE-derived and normal-derived platelet-binding anti-DNA autoantibodies may be due to antigen-selected mutations in the CDR2H and specific amino acid motifs in the CDR3H.
7553999 Clindamycin-induced neuromuscular blockade. 1995 Jul The purpose of this article is to report the case of a patient who developed prolonged neuromuscular block after a large dose of clindamycin (2400 mg). A 58-yr-old, 65 kg woman with severe rheumatoid arthritis was admitted for wrist arthrodesis. After d-tubocurarine (3 mg) and fentanyl (1.5 micrograms.kg-1), anaesthesia was induced with thiopentone (4 mg.kg-1) followed by succinylcholine (1.5 mg.kg-1) and was maintained with N2O in O2 and isoflurane (0.75-1.0% end tidal) and ventilation was controlled. No further neuromuscular relaxants were given although full return of neuromuscular activity in response to train-of-four and 100 Hz tetanic stimulation was observed after succinylcholine. An overdose of clindamycin (2400 mg, instead of the intended 600 mg) was given i.v. soon after the start of surgery. At the end of surgery, 75 min later, the patient made no attempt at spontaneous ventilation, was unresponsive to painful stimuli and naloxone (0.2 mg i.v.) was ineffective. Controlled ventilation was continued in the Recovery Room where neuromuscular testing showed a train-of-four ratio of 0.27 which improved to only 0.47 five minutes after calcium chloride (1.5 mg.kg-1 i.v.), and to 0.62 after edrophonium (20 mg) and neostigmine (2 mg). Nine hours later the patient began to cough, the TOF had returned to 1.0 and two hours later the trachea was extubated and spontaneous ventilation was resumed. Large doses of clindamycin can induce profound, long-lasting neuromuscular blockade in the absence of non-depolarizing relaxants and after full recovery from succinylcholine has been demonstrated.