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ID PMID Title PublicationDate abstract
1381760 Adenosine 3':5'-cyclic monophosphate inhibits in vitro angiogenesis induced by endothelial 1992 May The formation of new blood capillaries (angiogenesis) occurs in response to angiogenic factors released by either normal or tumoral cells. In the present study, we cultured human umbilical vein endothelial cells (HUVEC) on collagen gels and aimed to clarify the effects of cyclic nucleotides on angiogenesis induced by endothelial cell growth factor (ECGF). HUVEC invaded the underlying collagen matrix and formed tube-like structures when ECGF was added. ECGF (9.4 to 75 micrograms/ml) induced angiogenesis in a concentration-dependent manner; the effect reached a plateau at 75 micrograms/ml. Cyclic AMP (10(-3) M), dibutyryl cyclic AMP (10(-3) M), 8-bromo cyclic AMP (10(-5) M) and Sp-cAMPS (10(-3) M), a stimulator of cyclic AMP-dependent protein kinase, each significantly inhibited ECGF-induced angiogenesis by 64.2, 86.1, 46.5, 74.7%, respectively. Forskolin and cholera toxin, which are activators of adenylate cyclase, did not inhibit ECGF-induced angiogenesis. Dibutyryl cyclic GMP (10(-4), 10(-3) M) also did not affect the formation of capillary-like tubes induced by ECGF. In conclusion, cyclic AMP, but not cyclic GMP, inhibits angiogenesis in vitro. This antiangiogenic activity may be applicable to the treatment of such conditions as solid tumors, diabetic retinopathy and rheumatoid arthritis in which the suppression of angiogenesis is important.
9052874 The function of the soluble IL-6 receptor in vivo. 1996 Dec Interleukin-6 (IL-6) is considered an important mediator of acute inflammatory responses. Moreover, IL-6 functions as a differentiation and growth factor of hematopoietic precursor cells, B-cells, T-cells, keratinocytes, neuronal cells, osteoclasts and endothelial cells. IL-6 exhibits its action via a receptor complex consisting of a specific IL-6 receptor (IL-6R) and a signal-transducing subunit (gp130). Soluble forms of both receptor components are generated by shedding and are found in patients with various diseases such as AIDS, rheumatoid arthritis and others. The function of the soluble IL-6R in vivo is unknown. To discriminate between the biologic function of hIL-6 alone and that of the hIL-6/hsIL-6R complex, mice transgenic for human IL-6, for the human soluble IL-6R and for both, human IL-6 and the human soluble IL-6R were analyzed and compared with nontransgenic littermates. While IL-6 transgenic mice exhibit elevated acute phase protein levels and develop plasmacytomas, hsIL-6R single transgenic mice are hypersensitized towards human IL-6, mounting an acute phase protein gene induction at significantly lower IL-6 dosages compared to control animals. Furthermore, in hsIL-6R transgenic mice, the acute phase response persists for a longer period of time and the IL-6 plasma half life was markedly prolonged. IL-6/sI1-6R mice, however, develop massive hepatosplenomegaly caused by extramedullary hematopoisis in these organs. In IL-6- and IL-6R-single transgenic mice, no such effects were observed. Our study discloses a novel biologic effect of the hIL-6/hsIL-6R complex, which is clearly distinct from that of hIL-6 alone. We provide evidence that the activation of the gp130 signal transducer represents a major stimulation of growth and differentiation of hematopoietic progenitor cells.
8917124 Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-este 1996 Nov Laboratory animal models and clinical studies suggest that dietary n-3 fatty acids are beneficial in diseases with an inflammatory component such as rheumatoid arthritis or psoriasis. In the present study we investigated the effect of purified docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on phorbol ester (TPA)-induced acute inflammation. Mice were fed for 6 weeks a diet containing 5% corn oil enriched with either 1% DHA or 1% EPA and compared with a group receiving 6% corn oil only. The dietary treatment with DHA or EPA elevated the n-3 polyunsaturated fatty acids as expected in the spleen and ear phospholipids, associated with a reduction in arachidonic acid levels. The degree of ear inflammation was quantified by measuring the four parameters including (1) edema as the increase in ear biopsy weight, (2) polymorphonuclear cell infiltration as myeloperoxidase activity (MPO) at the site of inflammation, (3) prostaglandin E2 (PGE2) and (4) leukotriene B4 (LTB4) concentrations in ear edema. The addition of DHA to the diet reduced significantly the edema formation and the MPO activity 24 h after TPA challenge. Both DHA and EPA significantly reduced the PGE2 and LTB4 levels compared with animals fed corn oil. This result suggests that DHA rather than EPA may be useful in the adjuvant treatment of diseases where acute inflammatory processes play a role.
9414456 Angiogenesis in the ovary. 1996 Sep In adult tissues, capillary growth (angiogenesis) occurs normally during tissue repair, such as in the healing of wounds and fractures. Inappropriate capillary growth is associated with various pathological conditions, including tumour growth, retinopathies, haemangiomas, fibroses and rheumatoid arthritis in the case of rampant capillary growth, and nonhealing wounds and fractures in the case of inadequate capillary growth. The female reproductive organs exhibit marked, periodic growth and regression, accompanied by equally striking changes in their rates of blood flow. It is not surprising, therefore, that they are some of the few adult tissues in which angiogenesis occurs as a normal process. Ovarian follicles and corpora lutea have been shown to contain and produce angiogenic factors. These angiogenic factors appear to be heparin-binding and to belong to the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) families of proteins. In addition, factors regulating gap junctional communication may play a critical role in coordinating the interactions between luteal vascular and nonvascular tissues. Further elucidation of the specific physiological roles of these factors in follicular and luteal growth, development and function will ultimately lead to improved methods for regulating fertility in mammals.
7673729 Monocyte Fc gamma receptor cross-linking induces IL-8 production. 1995 Sep 15 In response to bacterial cell wall products such as LPS, monocytes produce IL-8, a powerful neutrophil chemotaxin. However, in the absence of bacterial pathogens, immune complex-mediated diseases such as rheumatoid arthritis are associated with high levels of IL-8 in monocyte-rich compartments. Since it is known that IgG-containing immune complexes can recruit neutrophils via an Fc gamma R-dependent process, we hypothesized that cross-linking of monocyte Fc gamma receptors may induce IL-8. To test this hypothesis, peripheral blood mononuclear cells were evaluated for IL-8 induction in response to immobilized LPS-free pooled human IgG. Immobilized IgG, but not soluble IgG, induced IL-8 in a dose-dependent manner (p < 0.05, r = 0.99). This induction corresponded with an up-regulation in IL-8 steady state mRNA levels that peaked at 4 h. The released IL-8 was functional, since supernatants induced concentration-dependent neutrophil migration that was inhibited by a monoclonal anti-IL-8 Ab. Evaluation of purified monocytes for IL-8 production, as well as FACS analysis of IgG-stimulated PBMC preparations, demonstrated that monocytes are the principal IL-8 producer cell. Thus, monocyte Fc gamma R cross-linking induces biologically active IL-8, which may participate in the pathogenesis of immune complex-mediated diseases.
7867645 Refined crystal structure of the interleukin-1 receptor antagonist. Presence of a disulfid 1995 Feb 1 Interleukin-1 (IL-1) molecules are cytokines involved in the acute-phase response against infection and injury. Three naturally occurring IL-1 molecules are known, two agonists: IL-1 alpha and IL-1 beta, and one antagonist, the IL-1 receptor antagonist (IL-1ra). Although IL-1 action protects the organism by enhancing the response to pathogens, its overproduction can lead to pathology and has been implicated in disease states that include septic shock, rheumatoid arthritis, graft versus host disease and certain leukemias. The crystal structure of IL-1ra has been solved at 0.21-nm resolution by molecular replacement using the IL-1 beta structure as a search model. The crystals contain two independent IL-1ra molecules which are very similar. IL-1ra has the same fold as IL-1 alpha and IL-1 beta. The fold consists of twelve beta-strands which form a six-stranded beta-barrel, closed on one side by three beta-hairpin loops. Cys69 and Cys116 are linked via a disulfide bond and Pro53 has been built in the cis-conformation. Comparison of the IL-1ra structure with the IL-1 alpha and IL-1 beta structures present in the Protein Data Bank shows that a putative receptor interaction region, involving the N-terminus up to the beginning of strand beta 1 and the loops D and G, is very different in the three IL-1 molecules. Other putative interaction regions, as identified with mutagenesis studies, are structurally conserved and rigid, allowing precise and specific interactions with the IL-1 receptor.
7863039 [Tibiotarsal arthrodesis: value of external fixator associated with in situ cancellous bon 1995 Tibio-talar arthrodesis poses some problems and the most frequent are non-union and varus malalignment of the ankle joint. The aim of this report was to present a new technique of ankle joint arthrodesis. The principles of this procedure are as follows: firstly, the external fixation (A.L.J.) is framed, secondly, perpendicular cuts are made in the tibial plafond and talus through an anterior longitudinal approach; and thirdly, the gap is filled with cancellous bone graft which is taken preferably on the iliac crest. If the back-foot is not correctly lined up preoperatively, the external device is framed in two steps: the first step consists in putting the pins. Then perpendicular cuts are made, and the back-foot is correctly lined up using calcaneal pins. The second step consists in connecting tibial pins and foot pins using union-rods. The last step of the procedure is to fill the gap with cancellous bone graft. The external fixation device is removed after 45 days and a shortleg walking cast is put for 45 days. Between 1981 and 1992, 18 arthrodesis were performed on various diagnosis: 9 post-traumatic tibio-talar osteoarthritis, 4 residual neurologic diseases, 2 rheumatoid arthritis and 3 recent post-traumatic lesions. There were 17 patients (one bilateral case), 4 females and 13 males; the middle age at the time of operation was 44.5 years (20 to 60) and there were 10 right ankles and 8 left. The tibio-talar arthrodesis was performed alone in 14 cases, but it was associated with a talo-calcaneus arthrodesis in 4 cases. The after care was without complications except 3 pins infection which cured with antibiotics. All the cases had a good bony union within 3 to 6 months and the orientation of the backfoot was always satisfactory without varus malalignment. All the patients could put one's shoes without having recourse to orthopaedic shoes. In conclusion, this operative procedure seems to minimize the problems and pittfalls of the ankle arthrodesis.
8018391 Effect of p40tax trans-activator of human T cell lymphotropic virus type I on expression o 1994 Mar The possibility of a retroviral etiology has long been raised in a number of autoimmune disorders. More recently, Sjögren's syndrome and rheumatoid arthritis were noted in transgenic mice carrying the tax gene of human T cell leukemia virus type I (HTLV-I). To evaluate the involvement of HTLV-I Tax in autoimmunity, its effect on expression of autoantigens was investigated. A metallothionein promoter-driven p40tax expression plasmid, pMAXRHneo-1, was stably transfected into Molt4 and Jurkat cells and the p40tax protein was induced with CdCl2. trans-Activation or trans-repression of autoantigens by HTLV-I Tax was studied by Western blot analysis utilizing autoantigen-specific murine monoclonal and rabbit polyvalent antibodies as well as sera from 161 autoimmune patients. Induction of p40tax of HTLV-I had no significant effect on levels of expression of common autoantigens U1 snRNP, Sm, Ro, La, HSP-70, topoisomerase I/Scl70, PCNA, and HRES-1. Expression of two potentially novel autoantigens, 44 and 46 kDa, was induced by p40tax as detected by sera of progressive systemic sclerosis patients, BAK and VAR. By contrast, expression of 24- and 34-kDa proteins was suppressed in response to induction of p40tax as detected by sera of systemic lupus erythematosus patients PUS and HOR. Because none of these patients were infected by HTLV-I, a protein functionally similar to p40tax may be involved in eliciting autoantigen expression and a subsequent autoantibody response in a minority of patients with PSS and SLE. Sera of autoimmune patients may also be utilized to detect novel proteins trans-activated or trans-repressed by p40tax of HTLV-I.
8252809 The gamma delta T cell repertoire in Graves' disease and multinodular goitre. 1993 Dec gamma delta T cells are a subset of T cells with unknown function, and restriction of the gamma delta T cell receptor (TCR) repertoire has been described in rheumatoid arthritis and multiple sclerosis. Elevated numbers of gamma delta T cells have been reported in the peripheral blood and thyroids of patients with Graves' disease. We have carried out flow cytometric analysis on peripheral blood mononuclear cells (PBMC) and intrathyroidal lymphocytes (ITL) from 12 patients with Graves' disease and nine patients with multinodular goitre (MNG), a thyroid disease of unknown etiology. There was no significant difference between the proportion of gamma delta T cells in the PBMC of Graves' and MNG patients, nor between the PBMC and ITL populations in either patient group. We have also carried out polymerase chain reaction amplification on RNA prepared from matched PBMC, ITL and the activated (CD25+) subset of ITL using six TCR V delta-family specific primers. Although there were differences in the amounts of each V delta transcript amplified from PBMC and ITL, there was no difference between the two patient groups. No consistent differences were therefore found between the gamma delta T cell populations in Graves' and MNG patients, arguing against the direct involvement of this T cell subset in the pathogenesis of Graves' disease.
8327097 Atlanto-axial stabilization with posterior transarticular screw fixation: technical descri 1993 Jun Magerl's technique of combining C1-C2 posterior screw fixation with a supplemental bone-wire fusion has been advocated for the management of atlanto-axial instability. Between October 1990 and August 1992, a modification of this technique was used in the treatment of 22 patients with this disorder. In the absence of spinal deformity or neoplastic disease, screw fixation and bony fusion were used alone without associated wiring, thus avoiding the risk of neural injury resulting from the sublaminar passage of wire and the retrodisplacement of ventral structures. Patient ages ranged from 30 months to 80 years; follow-up ranged from 5 to 27 months, with a mean of 14.9 months. The causes of the instabilities were as follows: eight cases of nonunion of Type II odontoid fracture, four cases of rheumatoid arthritis, three cases of tumor, two cases of ligamentous instability, two cases of pseudoarthrosis after bone-wire fusion, two cases of halo noncompliance, and one case of Os odontoideum. All 20 patients who underwent fusion were placed in a Philadelphia collar for 12 weeks. Nineteen of 20 (95%) patients achieved solid fusion. Twenty-one of 22 (95%) had significant reduction in preoperative pain. No patient developed myelopathy or bulbar findings. The one intraoperative complication was an inability to achieve secure screw purchase on one side that required unilateral screw placement with a Gallie fusion-using cable. Postoperative complications included one patient with a superficial wound infection that resolved after local debridement and antibiotics and suboccipital numbness in two patients. Progression of spinal deformity, screw pullout or breakage, and neurological or vascular complications did not occur.(ABSTRACT TRUNCATED AT 250 WORDS)
8510347 [Occupational diseases caused by exposure to sensitizing metals]. 1993 Mar Diseases caused by occupational exposure to sensitizing metals including platinum (Pt), rhodium (Rh), nickel (Ni), chromium (Cr), cobalt (Co), gold (Au), mercury (Hg), zirconium (Zr) and beryllium (Be) are reviewed. Allergic reactions induced by the metals are described according to the classification by Coombs and Gell. Metals with unproven sensitizing potential are not discussed if reports on these are either very rare or devoid of convincing evidence for allergic involvement. The sensitizing metals are haptens which are not themselves able to act as antigens. There is evidence that combination of the metals with circulating or tissue protein gives rise to new antigens. An alternative hypothesis is that these metals interfere with the antigen recognition step of the immune response. Immunomodulatory effects or immunotoxicity of the metals may be also involved in metal-induced hypersensitivity. Occupational exposure to Pt, Rh, Ni, Cr, and Co causes allergic asthma via type I allergic reaction in which serum from affected individuals shows specific IgE antibodies against mental-human serum albumin conjugates. Some rheumatoid arthritis patients treated with gold salt therapy develop glomerulonephritis, thrombocytopenia, or agranulocytosis, which arise from type II and/or type III allergic reactions. Occupational exposure to mercury causes glomerulonephritis in which involvement of type III reaction is suggested. Type IV hypersensitivity reaction of the skin also takes place following exposure to the metals: allergic contact dermatitis is evoked by exposure to Ni, Cr, Co, Rh, and Hg; cutaneous granuloma is formed by contact with Zr and Be. Be is also a sensitizer of the lungs, resulting in granulomatous disease. Diagnosis of metal-induced allergic diseases is made on the basis of allergological tests with metal antigens including skin tests, radioallergosorbent test for specific antibody, lymphocyte transformation test, macrophage migration inhibition test, and provocation test. Atopy is a predisposing factor and smoking is a risk factor for developing metal-induced asthma. Evidence for genetic factors in the development of metal contact dermatitis is conflicting, although animal models implicate genetic factors in skin sensitization with some metals and respiratory sensitization with Be. Skin irritation, forearm injury, complication with atopic dermatitis and concomitant sensitization to other agents are determinants for prognosis of the dermatitis. Epidemiological reports of occupational diseases from allergic reactions to metals in industries are reviewed with respect to prevalence and allergic manifestations. There is a report on a clinical trial of hyposensitization with Pt in a platinum asthma patient. Predictive methods for evaluating sensitization potential of metals have been developed and new methods, which quantify potential more objectively, are sought.
8429822 Inhibition by glucocorticoids of the formation of interleukin-1 alpha, interleukin-1 beta, 1993 Feb The mechanism by which glucocorticoids inhibit interleukin (IL)-1 and IL-6 formation in human monocytes and a promonocytic cell line activated by Escherichia coli lipopolysaccharide was analyzed. Dexamethasone (DEX) decreased levels of IL-1 alpha and IL-1 beta mRNAs in a dose-related fashion. The DEX-induced decrease in levels of IL-1 alpha and IL-1 beta mRNAs was abolished by the steroid receptor antagonist RU486. The levels of IL-1 alpha and IL-1 beta proteins within the cells and of IL-1 beta in the culture medium were decreased by DEX to comparable extents, so that DEX had no detectable effect on cytokine secretion. DEX did not influence lipopolysaccharide-induced transcription of the IL-1 beta gene in monocytes. However, DEX markedly decreased the stability of IL-1 beta mRNA, as shown both by steady state measurements and by pulse-labeling. DEX-induced instability of IL-1 beta mRNA required protein synthesis. DEX was also found to be a potent inhibitor of IL-1-induced expression of the IL-6 gene in connective tissue-type cells from the synovium of patients with rheumatoid arthritis. Inhibition of the formation of proinflammatory cytokines, including IL-1 beta and tumor necrosis factor-alpha, is a mechanism by which glucocorticoids exert anti-inflammatory effects. Inhibition by glucocorticoids of the expression of IL-1 alpha in antigen-presenting cells could decrease the capacity of the cells to stimulate the proliferation of T lymphocytes. This activity, as well as inhibition of the production and effects of IL-1 beta, including induced formation of IL-6 and of certain lymphokines, could explain the immunosuppressive effects of glucocorticoids.
1580290 Angiotensin-converting enzyme inhibition in mild hypertension with concomitant diseases an 1992 Apr 27 Despite a marked reduction in cardiovascular morbidity and mortality, treated hypertensive patients remain at increased risk of coronary artery disease and its complications compared with untreated normotensive subjects. Mild hypertension is often associated with other, usually chronic, diseases. The failure of first-line antihypertensive therapy to deal adequately with concomitant disease and associated therapy might account for the poor improvement in the cardiovascular prognosis. This possibility has been addressed in an ongoing trial of novel design, the Perindopril Therapeutic Safety Study, a multicenter, double-blind, randomized and placebo-controlled trial to determine the safety, efficacy, and interaction of angiotensin-converting enzyme (ACE) inhibition with eight of the most common concomitant diseases and their therapies. A total of 480 male and female patients (60 per disease group) aged 30-70 years, with a diastolic pressure of 90-104 mm Hg, were included after a 3-week placebo run-in if they satisfied standard criteria for any of the following: hyperlipidemia, type II diabetes, ischemic heart disease, cardiac arrhythmia, peripheral arterial disease, nephropathy with proteinuria, chronic obstructive lung disease, or rheumatoid arthritis. Of these, 460 patients have completed the 6-week double-blind phase (comprising two assessments, at 3 and 6 weeks), and are currently undergoing assessments every 3 months over a 1-year follow-up period. The end points include the incidence of progression or improvement in concomitant disease, the incidence of positive or negative interaction between ACE inhibition and concomitant therapy, change in blood pressure, adverse biochemical and hemodynamic reactions, self-reported side effects, and quality of life indices. Interim results for the 6-week double blind phase will shortly be available. However, the desirability and feasibility of conducting a study according to this novel design have already been proved.
8805676 Anti-IL-8 autoantibodies in alveolar fluid from patients with the adult respiratory distre 1996 Sep 15 IL-8 is a potent neutrophil attractant and activator. IL-8 has been reported to be involved in the pathogenesis of several diseases, including rheumatoid arthritis, sepsis, psoriasis, and the adult respiratory distress syndrome (ARDS). Our previous studies demonstrated that high concentrations of IL-8 were present in alveolar fluids from patients with ARDS and were associated with increased mortality. In this study we report that a major portion of IL-8 in bronchoalveolar fluids from patients with ARDS is associated with anti-IL-8 autoantibody (anti-IL-8:IL-8 complexes). Free autoantibodies that recognize IL-8 were also detected in these fluids. Next, we examined the properties of anti-IL-8 autoantibodies present in lung fluids from ARDS patients and compared them with autoantibodies from normal plasma and arthritic synovial fluids. The anti-IL-8 autoantibody was polyclonal, and IgG3 and IgG4 were the primary IgG subclasses. Anti-IL-8:IL-8 complexes consisted of one IgG and one IL-8 molecule. In addition, anti-IL-8 autoantibody bound IL-8 with a high affinity (approximately 10(-12) M) and inhibited IL-8 interaction with its specific receptors on neutrophils. The results suggest that anti-IL-8 autoantibodies may regulate IL-8 activity.
8751689 Functional abnormalities of the esophagus: a prospective analysis of radiographic findings 1996 Sep OBJECTIVE: The prevalence and severity of functional abnormalities of the esophagus seen on fluoroscopic examination were compared with the age and symptoms of the patients. SUBJECTS AND METHODS: The esophagus was examined radiographically in 139 consecutive outpatients 19-84 years old. All patients completed a data sheet about their symptoms, and medical records were reviewed to determine the main indication for the examination. Videofluoroscopy was used to evaluate primary peristalsis, proximal escape, and tertiary activity in the esophagus. The severity of proximal escape and activity was classified. RESULTS: Patients were categorized into three age groups: 39 years old or younger (n = 33); from 40 to 60 years old (n = 55); and 61 years old or older (n = 51). Abnormal esophageal motility, defined as disruption of peristalsis on two or more of five swallows, was found in 24% of patients 39 years old or younger, 36% of patients from 40 to 60 years old, and in 49% of patients 61 years old or older (p > .05). However, evaluation of the number of disrupted peristaltic swallows by age revealed 18% abnormal swallows in patients 39 years old or older, 27% in patients from 40 to 60 years old, and 37% in patients 61 years old or older (p < .01). Proximal escape and tertiary contractions increased significantly with the age of the patient. Regardless of age, proximal escape was seen in 79% of swallows and tertiary contractions were seen in 48% of swallows with disrupted peristalsis. The prevalence and severity of proximal escape and tertiary contractions increased in the older patients. Symptoms had no correlation with status of esophageal motility (p > .05). In 22 patients with secondary diseases, including rheumatoid arthritis and diabetes mellitus, those diseases showed no correlation with the status of esophageal motility. CONCLUSION: The prevalence of functional abnormalities of the esophagus increased with age. Most patients with abnormal swallows showed proximal escape with or without tertiary activity. Patients' symptoms and other diseases did not correlate with the status of their esophageal motility.
8860695 Peptide epitope binding specificity and V K and V H gene usage in a monoclonal IgM natural 1996 May Autoantibodies (AAbs) to T cell receptor (TCR) determinants are produced in humans during the course of rheumatoid arthritis and systemic lupus erythematosus as well as in retroviral infections. We have examined the binding specificity of a panel of monoclonal antibodies derived from mutant viable motheaten (mev) mice against several TCR peptide determinants representing the complementary determining region 1 (CDR1) regions of various Vbeta families, and have identified one mAb, UN37-5, that shows high affinity binding with specificity for two CDR1 peptide determinants. The light and heavy chain V genes of UN37-5 were sequenced and compared to known V genes. The UN37-5 V H gene sequence represents the V H J6O6 family and is most similar to a previously reported V H gene derived from a germ line DNA fragment representing a unique J606 family V H gene. This germ line V H gene is also used by previously characterized mev derived mAbs directed against thymocyte and RBC antigens. The UN37-5 V L gene sequence represents the V K 4/5 gene family. It has 87% homology with the V K Ox-1 germline gene. The UN37-5 V K sequence has greater than 95% identity at the amino acid level with VK L chains from IgM hybridomas specific for DNA and the influenza virus hemagglutinin. The specificity of this AAb is determined by the V H CDR3 and a V K chain which has not been utilized in previously reported mev autoantibodies.
8620293 Nitric oxide production in cells derived from the human joint. 1996 Mar We have investigated the ability of cells derived from the human joint to generate nitric oxide (NO). Synovial fibroblasts, articular chondrocytes and osteoblasts were cultured from tissues of patients undergoing hip replacement surgery, and synovial fluid leucocytes were obtained from patients undergoing joint aspiration. There was little spontaneous generation of NO by any of the cells after culture, but synovial fibroblasts, articular chondrocytes and osteoblasts all produced large quantities of NO in response to a cytokine mix of interleukin (IL)-1 beta + tumour necrosis factor alpha (TNF alpha) + interferon (IFN gamma). Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed the presence of mRNA transcripts for the inducible isoform of NO synthase in cytokine-stimulated but not in unstimulated cells. In contrast, leucocytes from synovial fluid did not produce NO either spontaneously or after cytokine stimulation, and mRNA for inducible NO synthase (iNOS) was not detected in these cells even by nested PCR. There were significant differences in the regulation of NO production between chondrocytes and other cells. Only chondrocytes generated NO in response to IL-1 beta or TNF alpha alone, whereas synovial fibroblasts and osteoblasts required the presence of at least two cytokines to generate NO. Dexamethasone (10(-6)M) had a small but significant inhibitory effect on NO production by chondrocytes, synovial fibroblasts and osteoblasts. Our results indicate that several cells within the human joint have the potential to generate NO in the presence of an appropriate pro-inflammatory cytokine stimulus, while leucocytes in synovial fluid are not a significant source of NO. The data support suggestions that NO is produced within the inflamed joint in diseases such as rheumatoid arthritis.
9062847 Species differences in the renal toxicity of the antiarthritic drug, gold sodium thiomalat 1996 Two gold compounds, gold sodium thiomalate (AuTM) and auranofin, are presently in clinical use in therapy of rheumatoid arthritis. In these studies, AuTM administered to Sprague-Dawley rats and three strains of mice, Swiss-Webster, C3H/HeJ, and DBA/2J, were studied with regard to its effect on liver and renal monooxygenases, metallothionein contents, and serum levels of alanine aminotransferase and urea nitrogen. These effects of AuTM were compared to those of cadmium, since the latter metal has exhibited tissue and species differences in the induction of metallothionein. Benzo(a)pyrene hydroxylase and benzphetamine N-demethylase activities were not altered by AuTM in livers of rats and the three strains of mice. Benzo(a)pyrene hydroxylase activity was significantly decreased in rat kidney, whereas this enzyme activity was not affected in the kidneys of mice. In rats, AuTM caused a sevenfold induction in liver metallothionein, while in mice, liver metallothionein was induced twofold in Swiss-Webster mice and about fivefold in the inbred strains. AuTM caused minimal changes in renal metallothionein contents in the three strains of mice studied. Serum alanine amino-transferase, an indicator of hepatotoxicity, was not altered by AuTM in rats and mice studied. Blood urea nitrogen, an indicator of kidney dysfunction, was increased threefold in rats, but not in AuTM-treated mice. These data demonstrate that AuTM, a nephrotoxic agent in rats and humans, showed no nephrotoxic effects in the mouse strains studied here.
8569199 The temporal and spatial vascular endothelial growth factor expression in retinal vasculog 1996 Jan Vascular endothelial growth factor (VEGF) has been identified as an endothelial cell-specific mitogen with potent angiogenic properties. VEGF is overexpressed in pathologic angiogenesis observed in tumor growth, rheumatoid arthritis, and retinal angiogenic diseases such as diabetic retinopathy and retinopathy of prematurity. VEGF expression in physiologic angiogenesis, i.e., vasculogenesis, has also been reported in the embryonic organs such as brain, kidney, spleen, and lung. However, the details of VEGF expression in vasculogenesis remain largely unclear. To determine if VEGF contributes to vasculogenesis in the developing tissues, VEGF expression was studied by both immunohistochemistry and in situ hybridization in newborn rat retinas on postnatal days 3, 7, 14, and 30. Vasculogenesis was assessed by both the ink perfusion method and a histologic examination. To identify the cell types of VEGF-expressing cells, immunohistochemistry for cell markers such as glial fibrillary acidic protein and von Willebrand factor was performed. On postnatal days 3 and 7, when retinal vasculogenesis was active, VEGF mRNA and protein(s) were prominently expressed in the ganglion cell and the inner nuclear layers. In rats, as well as humans, these two layers are where the retinal vessels develop, and these two layers depend solely on the retinal vessels. In addition to the ganglion and the inner nuclear layers, VEGF protein(s) were located in the endothelial cells of the developing vessels and the angioblasts, i.e., endothelial precursors. On postnatal day 14, when vasculogenesis became inactive, VEGF mRNA expression markedly decreased. These results indicated that VEGF expression in the developing retinas is temporally and spatially correlated with retinal vasculogenesis.
7492771 Salicylates inhibit lipopolysaccharide-induced transcriptional activation of the tissue fa 1995 Dec 1 Binding of plasma Factor VII/VIIa to the tissue factor (TF) receptor initiates the coagulation protease cascades. TF expression by circulating monocytes is associated with thrombotic and inflammatory complications in a variety of diseases. Transcriptional activation of the human TF gene in monocytic cells exposed to bacterial lipopolysaccharide (LPS) is mediated by binding of c-Rel/p65 heterodimers to a kappa B site in the TF promoter. Here, we report that a family of anti-inflammatory agents, known as the salicylates, inhibited LPS induction of TF activity and TF gene transcription in human monocytes and monocytic THP-1 cells at clinically relevant doses. Furthermore, sodium salicylate blocked the LPS-induced proteolytic degradation of I kappa B alpha, which prevented the nuclear translocation of c-Rel/p65 heterodimers. In contrast, two other nonsteroidal anti-inflammatory drugs, ibuprofen and indomethacin, did not inhibit LPS induction of the TF gene. These results indicated that salicylates inhibited LPS induction of TF gene transcription in monocytic cells by preventing nuclear translocation of c-Rel/p65 heterodimers. The clinical benefits of salicylates in the treatment of several diseases, including atherosclerosis and rheumatoid arthritis, may be related to their ability to reduce monocyte gene expression.