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ID PMID Title PublicationDate abstract
10069412 Anti-rheumatic compound aurothioglucose inhibits tumor necrosis factor-alpha-induced HIV-1 1999 Feb NF-kappaB is a potent cellular activator of HIV-1 gene expression. Down-regulation of NF-kappaB activation is known to inhibit HIV replication from the latently infected cells. Gold compounds have been effectively used for many decades in the treatment of rheumatoid arthritis. We previously reported that gold compounds, especially aurothioglucose (AuTG) containing monovalent gold ion, inhibited the DNA-binding of NF-kappaB in vitro. In this report we have examined the efficacy of the gold compound AuTG as an inhibitor of HIV replication in latently infected OM10.1 and Ach2 cells. Tumor necrosis factor (TNF)-alpha-induced HIV-1 replication in OM10.1 or Ach2 cells was significantly inhibited by non-cytotoxic doses of AuTG (>10 microM in OM10.1 cells and >25 F.M in Ach2 cells), while 25 microM of the counter-anion thioglucose (TG) or gold compound containing divalent gold ion, HAuCl3, had no effect. The effect of AuTG on NF-kappaB-dependent gene expression was confirmed by a transient CAT assay. Specific staining as well as electron microscopic examinations revealed the accumulation of metal gold in the cells, supporting our previous hypothesis that gold ions could block NF-kappaB-DNA binding by a redox mechanism. These observations indicate that the monovalent gold compound AuTG is a potentially useful drug for the treatment of patients infected with HIV.
9949509 [Viral hepatitis delta in the republic of Belarus]. 1998 Nov 26,740 blood donors and persons of high risk groups with respect to HBV infection, residing in different regions of Belarus, were examined for the presence of HBsAg in 1983-1997. Of these, 1372 persons (5.1%) were found to have HBsAg, and out of 1081 HBsAg-positive persons anti-HDV antibodies (Ab) were detected in 96 persons (8.9%). In spite of a decrease in acute virus hepatitis B morbidity and in HBsAg carriership, the occurrence of anti-HBV Ab remained stable during the period of 16 years and was equal, on the average, about 4% among asymptomatic HBsAg carriers. Patients having tuberculosis, rheumatoid arthritis, diabetes mellitus, hematological diseases, chronic hepatitides and cirrhosis of the liver were an important reservoir of HBV and HDV infections for regions with the low level of the spread of HBV. A decrease in the detection rate of anti-HDV Ab in patients with cirrhosis of the liver from 47.6% to 15.4% was noted. In 1991-1997 a decrease in the detection rate of anti-HDV Ab in patients with chronic hepatic lesions in comparison with 1983-1990 was observed, and in the age group older than 50 years this decrease was from 33.3% to 8.3%. This difference was particularly pronounces in patients with cirrhosis of the liver: 53.9% and 7.7% respectively.
9918599 Oral administration of leflunomide (HWA486) results in prominent suppression of immunoglob 1999 Feb Leflunomide, a drug being developed for use in the treatment of rheumatoid arthritis, was evaluated in an ovalbumin (OVA)-induced rat type 1 allergy model. In a dose of 1 mg/kg/day, it strongly suppressed the formation of OVA-specific IgE, thus preventing the elevation of the plasma histamine level and induction of anaphylactic shock observed after i.v. challenge with OVA. Studies on leflunomide's effects on the secondary antibody response showed that administration during the primary immune response remarkably diminished the secondary antibody responses, except IgM, even without further drug administration. Furthermore, when administered during the secondary response after rechallenge, both the total IgE and OVA-specific IgE serum levels declined rapidly to nearly baseline levels. Although OVA-specific IgG1, IgG2a, and IgM did not decrease from their primary response levels, these classes' secondary responses were strongly suppressed. In an in vitro study, the proliferation and antibody production of OVA-stimulated spleen cells, derived from Brown Norway rats, were strongly inhibited by A77 1726, leflunomide's active metabolite. When uridine was added to the cell culture, this molecule's effect on cell proliferation was completely restored, whereas the antibody production was partially restored. These findings are consistent with data indicating that leflunomide is a dihydroorotate dehydrogenase inhibitor. Taken together, the above findings suggest the therapeutic potential of leflunomide against type 1 allergic diseases.
9685351 Human placenta thioredoxin reductase. Isolation of the selenoenzyme, steady state kinetics 1998 Aug 7 Human thioredoxin reductase is a pyridine nucleotide-disulfide oxidoreductase closely related to glutathione reductase but differing from the latter in having a Cys-SeCys (selenocysteine) sequence as an additional redox center. Because selenoproteins cannot be expressed yet in heterologous systems, we optimized the purification of the protein from placenta with respect to final yield (1-2 mg from one placenta), specific activity (42 units/mg), and selenium content (0.94 +/- 0.03 mol/mol subunit). The steady state kinetics showed that the enzyme operates by a ping-pong mechanism; the value of kcat was 3330 +/- 882 min-1, and the Km values were 18 microM for NADPH and 25 microM for Escherichia coli thioredoxin. The activation energy of the reaction was found to be 53.2 kJ/mol, which allows comparisons of the steady state data with previous pre-steady state measurements. In its physiological, NADPH-reduced form, the enzyme is strongly inhibited by organic gold compounds that are widely used in the treatment of rheumatoid arthritis; for auranofin, the Ki was 4 nM when measured in the presence of 50 microM thioredoxin. At 1000-fold higher concentrations, that is at micromolar levels, the drugs also inhibited human glutathione reductase and the selenoenzyme glutathione peroxidase.
9629626 The clinical significance of antinuclear antibodies in connective tissue disease. 1998 May 8 Antinuclear antibodies (ANA) are often present in connective tissue diseases. In 279 non-selected patients with connective tissue disease, inflammatory and degenerative joint disease, in some patients with chronic infectious diseases and malignancies and in the presence of some unclear pathologic conditions in patients whose serum reacted positively to ANA, we analyzed the type of immunofluorescence and the presence of extractable antinuclear antibodies (ENA). In systemic lupus erythematosus, the prevailing immunofluorescence is type H (homogenous) (60.6%), anti-Ro/SS-A appears in 24.2%, anti-Sm and anti-RNP in 12.1%. In Sjögren's syndrome, type S prevails (47.6%), anti- Ro/SS-A and anti-La/SS-B are present in 52.4%, only anti-Ro/SS-A in 28.6%. In systemic sclerosis, the prevailing immunofluorescence is type S (37.5%), in 75% a positive anti-Scl-70 antibody is present. In mixed connective tissue disease, anti-RNP appears in 85.7%. In dermatopolymyositis, the anti-Jo-1 antibody is present in 33.3%. In undifferentiated connective tissue disease, type S immunofluorescence appears in 70%. In rheumatoid arthritis the prevailing immunofluorescence is type H (homogenous) (46.4%) and type S (speckled) (41.0%), while the presence of ENA is rare (anti-Ro/SS-A in 4.6%). In spondylarthritis, type S immunofluorescence appears most often (62.5%). Patients with chronic infectious disease, malignancies, undefined conditions and degenerative joint disease present with various types of immunofluorescence; the presence of ENA is extremely rare in these patients. The results of this study underline the significance of ANA and, particularly ENA, in the diagnosis of connective tissue disease. These antibodies however, can also be identified in various infectious and malignant diseases as well as in inflammatory and degenerative joint diseases.
9598879 Quantitative rheumatology: a survey of outcome measurement procedures in routine rheumatol 1998 May OBJECTIVE: To assess the extent to which quantitative clinical measurement is performed by rheumatologists in the longitudinal followup of patients with rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis (AS), and fibromyalgia (FM) in routine outpatient practice in Canada. METHODS: A cross sectional postal survey was conducted using an 18 item self-administered questionnaire sent to Canadian Rheumatology Association members. RESULTS: Rheumatologists (response rate 85%) were more likely to longitudinally follow patients with RA and AS than those with OA or FM. There was a high degree of variability in the methods used to monitor patients longitudinally. Many measures used in clinical research were used infrequently in routine clinical practice. In general, the major health status measures surveyed were not used in clinical monitoring. There was a high level of agreement (>80%) that the characteristics required of an outcome measure for use in clinical practice should include simplicity, brevity, ease of scoring, reliability, validity, and sensitivity to change. CONCLUSION: The majority of Canadian rheumatologists perform outcome measurement during the longitudinal followup of their outpatients with RA, AS, OA, and FM. However, the process lacks standardization. High performance health status measures, developed for clinical research, have not been widely adopted in rheumatology practices. There is agreement on the characteristics required by Canadian rheumatologists for measurement procedures used in routine clinical care. Quantitative measurement in clinical practice using standardized procedures is an attainable, but as yet, unrealized opportunity.
9384562 Structure of the complex of leech-derived tryptase inhibitor (LDTI) with trypsin and model 1997 Nov 15 BACKGROUND: Tryptase is a trypsin-like serine proteinase stored in the cytoplasmic granules of mast cells, which has been implicated in a number of mast cell related disorders such as asthma and rheumatoid arthritis. Unlike almost all other serine proteinases, tryptase is fully active in plasma and in the extracellular space, as there are no known natural inhibitors of tryptase in humans. Leech-derived tryptase inhibitor (LDTI), a protein of 46 amino acids, is the first molecule found to bind tightly to and specifically inhibit human tryptase in the nanomolar range. LDTI also inhibits trypsin and chymotrypsin with similar affinities. The structure of LDTI in complex with an inhibited proteinase could be used as a template for the development of low molecular weight tryptase inhibitors. RESULTS: The crystal structure of the complex between trypsin and LDTI was solved at 2.0 A resolution and a model of the LDTI-tryptase complex was created, based on this X-ray structure. LDTI has a very similar fold to the third domain of the turkey ovomucoid inhibitor. LDTI interacts with trypsin almost exclusively through its binding loop (residues 3-10) and especially through the sidechain of the specificity residue Lys8. Our modeling studies indicate that these interactions are maintained in the LDTI-tryptase complex. CONCLUSIONS: The insertion of nine residues after residue 174 in tryptase, relative to trypsin and chymotrypsin, prevents inhibition by other trypsin inhibitors and is certainly responsible for the higher specificity of tryptase relative to trypsin. In LDTI, the disulfide bond between residues 4 and 25 causes a sharp turn from the binding loop towards the N terminus, holding the N terminus away from the 174 loop of tryptase.
10088775 Tumor necrosis factor alpha regulation of the FAS-mediated apoptosis-signaling pathway in 1999 Mar OBJECTIVE: Fas-mediated apoptosis is observed in synoviocytes of patients with rheumatoid arthritis (RA), but not in those of patients with osteoarthritis (OA). The present study was conducted to elucidate the mechanisms that initiate induction of Fas-mediated apoptosis in RA synoviocytes. METHODS: Cultured OA synoviocytes, which are insensitive to Fas-mediated apoptosis in spite of Fas antigen expression, were used in these experiments. Synovial cell proliferation and cytotoxicity studies were performed using MTS and lactate dehydrogenase release assays. Surface expression of Fas antigen was analyzed by flow cytometry. The expression and function of apoptosis-signaling molecules, such as caspase 8 and caspase 3, were examined by immunoblot analysis. RESULTS: Tumor necrosis factor alpha (TNFalpha) induced proliferation of cultured OA synoviocytes. Fas ligation with anti-Fas monoclonal antibody (mAb) resulted in cytotoxic activity against cultured OA synoviocytes that had been pretreated with TNFalpha for 5 days, but not those pretreated for 2 days. In contrast, anti-Fas mAb did not show a cytotoxic effect against untreated cultured OA synoviocytes. A gradual up-regulation of caspase 8 and caspase 3, which played a role in the caspase cascade for Fas-mediated apoptosis, was observed in TNFalpha-treated cultured OA synoviocytes. In addition, Fas ligation to TNFalpha-treated cultured OA synoviocytes induced activation of caspase 8 and caspase 3, with subsequent cleavage of poly(ADP-ribose) polymerase (PARP), a substrate of activated caspase 3. More importantly, Z-IETD-FMK, a caspase 8 inhibitor, and Ac-DEVD-CHO, a caspase 3 inhibitor, almost completely inhibited Fas-mediated apoptosis of TNFalpha-treated cultured OA synoviocytes, whereas Ac-YVAD-CHO, a caspase 1 inhibitor, did not. CONCLUSION: Our results clearly demonstrate that TNFalpha stimulates synovial cells to proliferate as well as sensitizes the cells for Fas-mediated apoptosis, at least in part by up-regulation and activation of caspase 8 and caspase 3. These findings suggest that TNFalpha may be one of the factors providing sensitization of synovial cells to Fas-mediated apoptosis in RA.
9663488 Vascular cell adhesion molecule 1 (CD106) on primary human articular chondrocytes: functio 1998 Jul OBJECTIVE: To investigate the expression of adhesion molecules belonging to the immunoglobulin superfamily on human primary articular chondrocytes and to determine their response pattern to cytokines with respect to the adhesion of lymphocytes. METHODS: The expression of adhesion molecules was studied by flow cytometry (cultured cells), immunohistochemistry (cartilage), reverse transcription-polymerase chain reaction, and Northern blotting. Adhesion of T cells to chondrocytes was measured using the Jurkat T cell line. RESULTS: Vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) were found to be constitutively expressed on large percentages of unstimulated chondrocytes in culture and in cartilage ex vivo. ICAM-2, ICAM-3, and very late activation antigen 4 (VLA-4; alpha4beta1 integrin), the ligand for VCAM-1, were not detected. Interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) further induced VCAM-1 and ICAM-1 messenger RNA and protein expression. Transforming growth factor beta (TGFbeta) had no effect on ICAM-1 and decreased the expression of VCAM-1. Another adhesion molecule, VLA-2 alpha2beta1 integrin) that was also expressed on unstimulated chondrocytes, was differentially regulated by cytokines. While neither IL-1beta nor TNFalpha had any effect on expression of VLA-2, TGFbeta markedly increased the alpha2 subunit of VLA-2. Adhesion of Jurkat T cells to chondrocytes was further induced by IL-1beta and TNFalpha. Pretreatment of chondrocytes with monoclonal antibodies to VCAM-1 and ICAM-1 inhibited adhesion of T cells to chondrocytes. CONCLUSION: VCAM-1, ICAM-1, and VLA-2 are constitutively expressed by human articular chondrocytes. Expression is regulated by cytokines. As shown for other chondrocyte genes, IL-1beta/TNFalpha and TGFbeta antagonistically modulate the expression of adhesion molecules. VCAM-1 and ICAM-1 contribute to adhesion of T lymphocytes to chondrocytes, and may thus participate in host defense mechanisms during inflammatory joint conditions such as rheumatoid arthritis and after cartilage transplantation.
9050861 DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, 1997 Mar 4 The product of the dek oncogene is the 43-kDa DEK nuclear protein. DEK was first identified in a fusion with the CAN nucleoporin protein in a specific subtype of acute myelogenous leukemia. DEK has also been shown to be an autoantigen in patients with pauciarticular onset juvenile rheumatoid arthritis. Further, the last 65 amino acids of DEK can partially reverse the mutation-prone phenotype of cells from patients with ataxia-telangiectasia. However, in spite of these significant disease associations, the function of DEK has remained unclear. The HIV-2 peri-ets (pets) site is a TG-rich element found between the two Elf-1 binding sites in the HIV-2 enhancer. The pets element mediates transcriptional activation whether the enhancer is stimulated by phorbol 12-myristate 13-acetate (PMA) alone, phytohemagluttinin (PHA) alone, PMA plus PHA, soluble antibodies to the T cell receptor, immobilized antibodies to the T cell receptor, or by antigen. Previously, we purified and characterized the pets factor, demonstrating that it is a 43-kDa nuclear protein. We now describe the identification of DEK as this 43-kDa pets factor. Using a modified Southwestern screening procedure, we find that DEK can recognize the pets element. We demonstrate the ability of recombinant DEK to bind specifically to the pets site using the electrophoretic mobility shift assay (EMSA) and DNase I footprinting. "Supershift" EMSA further confirms that DEK is the dominant protein binding to the pets site in T cell extracts. Our findings show that DEK is a site-specific DNA binding protein that is likely involved in transcriptional regulation and signal transduction. This has implications for multiple pathogenic processes, including hematologic malignancies, arthritis, ataxia-telangiectasia, and AIDS caused by HIV-2.
9696080 Posterior C1-C2 transarticular screw fixation for atlantoaxial arthrodesis. 1998 Aug OBJECTIVE: To assess the outcomes associated with C1-C2 transarticular screw fixation. METHODS: The clinical outcomes of 121 patients treated with posterior C1-C2 transarticular screws and wired posterior C1-C2 autologous bone struts were evaluated prospectively. Atlantoaxial instability was caused by rheumatoid arthritis in 48 patients, C1 or C2 fractures in 45, transverse ligament disruption in 11, os odontoideum in 9, tumors in 6, and infection in 2. RESULTS: Altogether, 226 screws were placed under lateral fluoroscopic guidance. Bilateral C1-C2 screws were placed in 105 patients; each of 16 patients had only one screw placed because of an anomalous vertebral artery (n = 13) or other pathological abnormality. Postoperatively, each patient underwent radiography and computed tomography to assess the position of the screw and healing. Most screws (221 screws, 98%) were positioned satisfactorily. Five screws were malpositioned (2%), but none were associated with clinical sequelae. Four malpositioned screws were reoperated on (one was repositioned, and three were removed). No patients had neurological complications, strokes, or transient ischemic attacks. Long-term follow-up (mean, 22 mo) of 114 patients demonstrated a 98% fusion rate. Two nonunions (2%) required occipitocervical fixation. In comparison, our C1-C2 fixations with wires and autograft (n = 74) had an 86% union rate. CONCLUSION: Rigidly fixating C1-C2 instability with transarticular screws was associated with a significantly higher fusion rate than that achieved using wired grafts alone. The risk of screw malpositioning and catastrophic vascular or neural injury is small and can be minimized by assessing the position of the foramen transversaria on preoperative computed tomographic scans and by using intraoperative fluoroscopy and frameless stereotaxy to guide the screw trajectory.
17008969 [The endoscopic release of the transverse carpal ligament for carpal tunnel syndrome.]. 1997 Jun GOAL OF SURGERY: Complete division of the flexor retinaculum for decompression of the medial nerve to restore normal neurologic function. INDICATIONS: Idiopathic and posttraumatic carpal tunnel syndrome. CONTRAINDICATIONS: Postoperative recurrence, carpal tunnel syndrome in patients with rheumatoid arthritis, with tumors or with carpal canal compromise due to bony causes. POSITIONING AND ANAESTHESIA: Supine General or regional anaesthesia. SURGICAL TECHNIQUE: Identification of the palmaris longus tendon. 1.5 cm long incision along the flexor crease of the wrist. If the palmaris longus is absent the incision should be made 1.5 cm medial to the flexor carpi radialis tendon. Introduction of the scope and exploration of the ulnar border of the carpal canal with a special instrument until the hook of the hamate has been identified. Endoscopic identification of the distal end of the retinaculum and insertion of the cutter. Complete division of the retinaculum. POSTOPERATIVE MANAGEMENT: Posterior plaster splint for 7 days. Elevation of the limb. Active exercises of fingers, elbow and shoulder and, after cast removal, also of the wrist. Lifting and carrying of heavy objects should be avoided for 4 to 6 weeks. POSSIBLE COMPLICATIONS: Injury of the median nerve or one of its branches, of the superficial palmar arch, and of the flexor tendons. RESULTS: Prospective randomized study of 120 patients of which 101 could be followed up. Forty-five patients (group A) had an open decompression and 47 (group B) were decompressed endoscopically. Average follow-up period for group A 271 days, for group B 275 days. Mean age of both groups: 53 years. There were 13 men and 41 women in group A and 17 men and 30 women in group B. No complications or night pain in either group. No significant difference in atrophy of the thenar eminence in the strength of the hand or in the 2 point discrimination. Results of pre- and postoperative nerve conduction and of temporary disability are listed in Figures 10 and 11. At follow-up 6 to 12 weeks postoperatively no difference could be found between the 2 groups in respect to scar pain, grip power and range of motion. Main advantage of the endoscopic approach: reduced postoperative pain and shorter disability.
11742275 Expression of IL-15 in inflammatory pulmonary diseases. 2001 Dec BACKGROUND: IL-15 is a T(H)1-related cytokine that shares many biologic activities with IL-2. Both cytokines bind a specific alpha subunit, and they share the same beta and gamma common receptor subunits for signal transduction. IL-15 has recently been shown to be upregulated in T cell-mediated inflammatory disorders, such as rheumatoid arthritis and inflammatory bowel diseases. However, the role and expression of IL-15 in inflammatory lung disease has not been investigated. OBJECTIVE: In the present study we have evaluated the expression of IL-15 mRNA and protein in bronchial biopsy specimens obtained from patients with sarcoidosis (n = 8), tuberculosis (n = 7), chronic bronchitis (n = 10), and bronchial asthma (n = 8) and compared its expression with that seen in normal control subjects (n = 11). METHODS: In situ hybridization and immunocytochemistry were used to detect the number of cells expressing IL-15 mRNA and protein, respectively, within sections of bronchial tissues from all subject groups. In addition, double immunocytochemistry was used to characterize the cellular source of IL-15. RESULTS: The number of IL-15(+) cells was significantly higher within tissue from patients with sarcoidosis, tuberculosis, and chronic bronchitis compared with that in asthmatic patients and normal control subjects. Similar results were obtained for IL-15 immunoreactivity by using immunohistochemistry. Furthermore, double immunostaining revealed that neutrophils and macrophages are the major source of IL-15. CONCLUSION: These results suggest that the expression of IL-15 may be associated with T(H)1-mediated chronic inflammatory diseases of the lung.
11722559 Kinetics of small molecule inhibitor binding to p38 kinase. 2001 Nov p38 mitogen-activated protein kinase (MAPK) (p38/p38-alpha/CSBP2/RK) has been implicated in the regulation of many proinflammatory pathways. Because of this, it has received much attention as a potential drug target for controlling diseases such as rheumatoid arthritis, endotoxic shock, inflammatory bowel disease, osteoporosis, and many others. A number of small molecule inhibitors of this kinase have been described, and in this paper we have used surface plasmon resonance to directly measure and quantitate their binding to p38. Despite the relatively low molecular mass (approximately 400 Da) of these inhibitors, specific binding can be observed. For the two most potent inhibitors studied, SB 203580 and RWJ 67657, dissociation constants, K(d)'s, of 22 and 10 nm, respectively, were obtained. These values closely match the IC(5)0 values observed in a cell-based TNF alpha release assay implying that p38 plays a major role in TNF alpha release. The association and dissociation rates for the binding of these inhibitors to p38 have also been quantitated. SB 203580 and RWJ 67657 have very similar association rates of around 8 x 10(5) m(-1) x s(-1), and the differences in affinity are determined by different dissociation rates. The weaker binding compounds have dissociation rates similar to SB 203580, but the association rates vary by an order of magnitude or more. The direct measurement of compounds binding to p38 may help in understanding the difference between potency and efficacy for these inhibitors. This in turn may yield clues on how to develop better inhibitors.
11710776 The impact of recent advances in immunology and cancer therapy on nuclear medicine. 2001 Oct The explosive expansion of knowledge in immunology in recent decades has already affected the research and practice of nuclear medicine in several ways. New hematopoietic cells have been isolated and their functions discovered, including hematopoietic stem cells and dendritic cells (DCs). Many new humeral factors have been found that have potent effects on cells, including cytokines, growth factors, and specialized proteins. Radiolabeled compounds are needed to follow the pharmacodynamics of the humeral factors and to follow the migration of mobile cells in animals and humans. In this article, only DCs, cytokines, and growth factors used clinically are discussed. DCs are essential for defense against infectious diseases. Autologous DCs cultured for a week and pulsed with tumor antigens have already proved highly immunogenic compared with other methods for activating cytotoxic T cells, and preliminary studies suggest that DCs are more potent for tumor cell killing than monoclonal antibodies. DCs, unfortunately, also play an important role in causing certain human diseases. In allograft transplants, residual donor DCs are responsible for the cellular rejection; if they could be eliminated, rejection could be prevented. These cells are also detrimental in rheumatoid arthritis, other autoimmune diseases, asthma, and chronic obstructive pulmonary disease. Cytokines such as interleukin-2 and such growth factors as granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor, administered to patients with malignancies to alleviate the leukopenia of chemotherapy agents, frequently alter the tissue distribution of radiopharmaceuticals; these alterations may be confused with disease.
11529926 Amphipathic variable region heavy chain peptides derived from monoclonal human Wegener's a 2001 Aug Amphipathic variable-region heavy chain 11-mer peptides from monoclonal human IgM antiproteinase-3 antibodies were studied for peripheral blood lymphocyte stimulation in 21 patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), connective tissue disease controls and normal control subjects. Positive T-cell activation was observed in most experiments with WG patients' lymphocytes using amphipathic VH-region peptides from four different human monoclonal anti-PR3 antibodies. Control peptides of the same length but without amphipathic characteristics along with other amphipathic peptides not derived from monoclonal anti-PR3 sequence were employed as controls. No significant lymphocyte stimulation was observed with normal controls, but positive stimulation with amphipathic VH peptides was also recorded in other connective tissue disease controls mainly patients with rheumatoid arthritis. Amphipathic peptides not derived from anti-PR3 sequence did not stimulate WG lymphocytes. Our findings indicate that lymphocyte reactivity as an element of cell-mediated immunity may be activated by amphipathic VH-region amino acid sequences of autoantibodies which are themselves associated with diseases such as WG.
11421342 A journey to the world of glycobiology. 2000 Jul Finding of the deletion phenomenon of certain oligosaccharides in human milk and its correlation to the blood types of the donors opened a way to elucidate the biochemical basis of blood types in man. This success led to the idea of establishing reliable techniques to elucidate the structures and functions of the N-linked sugar chains of glycoproteins. N-Linked sugar chains were first released quantitatively as oligosaccharides by enzymatic and chemical means, and labelled by reduction with NaB3H4. After fractionation, structures of the radioactive oligosaccharides were determined by a series of methods developed for the studies of milk oligosaccharides. By using such techniques, structural rules hidden in the N-linked sugar chains, and organ- and species-specific N-glycosylation of glycoproteins, which afforded a firm basis to the development of glycobiology, were elucidated. Finding of galactose deficiency in the N-linked sugar chains of serum IgG from patients with rheumatoid arthritis, and malignant alteration of N-glycosylation in various tumors opened a new research world called glycopathology. However, recent studies revealed that several structural exceptions occur in the sugar chains of particular glycoproteins. Finding of the occurrence of the Galbeta1-4Fucalpha1- group linked at the C-6 position of the proximal N-acetylglucosamine residue of the hybrid type sugar chains of octopus rhodopsin is one of such examples. This finding indicated that the fucosyl residue of the fucosylated trimannosyl core should no more be considered as a stop signal as has long been believed. Furthermore, recent studies on dystroglycan revealed that the sugar chains, which do not fall into the current classification of N and O-linked sugar chains, are essential for the expression of the functional role of this glycoprotein. It was found that expression of many glycoproteins is altered by aging. Among the alterations of the glycoprotein patterns found in the brain nervous system, the most prominent evidence was found in P0. This protein is produced in non-glycosylated form in the spinal cord of young mammals. However, it starts to be N-glycosylated in the spinal cord of aged animals. These evidences indicate that various unusual sugar chains occur as minor components in mammals, and play important roles in particular tissues.
11311743 Cyclooxygenase inhibitors--current status and future prospects. 2001 Feb Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase and subsequent downstream synthetases. Two closely related forms of the cyclooxygenase have been identified which are now known as COX-1 and COX-2. Both isoenzymes transform arachidonic acid to prostaglandins, but differ in their distribution and their physiological roles. Meanwhile, the responsible genes and their regulation have been clarified. COX-1, the pre-dominantly constitutive form of the enzyme, is expressed throughout the body and performs a number of homeostatic functions such as maintaining normal gastric mucosa and influencing renal blood flow and platelet aggregation. In contrast, the inducible form is expressed in response to inflammatory and other physiological stimuli and growth factors, and is involved in the production of the prostaglandins that mediate pain and support the inflammatory process. All the classic NSAIDs inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects are based on the inhibition of COX-2, but the gastrointestinal toxicity and the mild bleeding diathesis are a result of the concurrent inhibition of COX-1. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis. Apart from its involvement in inflammatory processes, COX-2 seems to play a role in angiogenesis, colon cancer and Alzheimer's disease, based on the fact that it is expressed during these diseases. The benefits of specific and selective COX-2 inhibitors are currently under discussion and offer a new perspective for a further use of COX-2 inhibitors.
11150459 Inflammatory pseudotumor of the alimentary tract: clinical and surgical experience. 2001 Jan BACKGROUND/PURPOSE: Initially described in 1937, inflammatory pseudotumor (IPT) inflammatory myofibroblastic tumor (IMT) or plasma cell granulomas are synonymous for an inflammatory solid tumor that contains spindle cells, myofibroblasts, plasma cells, and histocytes. Common sites of presentation include lung, mesentary, liver, and spleen; intestinal presentations are rare, and the etiology remains obscure. This report details the clinical and surgical experiences in 4 children with alimentary tract IPT at a single institution. METHODS: A retrospective chart review was conducted of pediatric patients with the pathologic diagnosis of IPT. RESULTS: Between 1990 and 1999, 4 patients (4 girls, ages 5 to 15 years) were identified with gastrointestinal tract origins of IPT. Symptoms at presentation included anemia (n = 4), intermittent abdominal pain (n = 3), fever (n = 3), weight loss (n = 2), diarrhea (n = 2), dysphagia (n = 1). Two patients had comorbid conditions of juvenile rheumatoid arthritis and mature B cell lymphoma. Three of 4 patients had elevated sedimentation rates. The sites of origin were the gastroesophageal junction, the colon, the rectum, and the appendix, with the referral diagnosis achalasia, perforated appendix, inflammatory bowel disease, and recurrent lymphoma, respectively. All were treated with aggressive surgical resection, and 3 girls have had no recurrences since the initial surgery. One patient had 3 recurrences within 8 months of presentation; she remains disease free 8 years later. CONCLUSIONS: IPT, although rare in the gastrointestinal tract, mimics more common problems. Successful surgical management is possible even in cases of multiple recurrences.
11036568 Three-dimensional finite element analysis of glenoid replacement prostheses: a comparison 2000 Aug Glenoid component loosening is the dominant cause of failure in total shoulder arthroplasty. It is presumed that loosening in the glenoid is caused by high stresses in the cement layer. Several anchorage systems have been designed with the aim of reducing the loosening rate, the two major categories being "keeled" fixation and "pegged" fixation. However, no three-dimensional finite element analysis has been performed to quantify the stresses in the cement or to compare the different glenoid prosthesis anchorage systems. The objective of this study was to determine the stresses in the cement layer and surrounding bone for glenoid replacement components. A three-dimensional model of the scapula was generated using CT data for geometry and material property definition. Keeled and pegged designs were inserted into the glenoid, surrounded by a 1-mm layer of bone cement. A 90 deg arm abduction load with a full muscle and joint load was applied, following van der Helm (1994). Deformations of the prosthesis, stresses in the cement, and stresses in the bone were calculated. Stresses were also calculated for a simulated case of rheumatoid arthritis (RA) in which bone properties were modified to reflect that condition. A maximum principal stress-based failure model was used to predict what quantity of the cement is at risk of failure at the levels of stress computed. The prediction is that 94 percent (pegged prosthesis) and 68 percent (keeled prosthesis) of the cement has a greater than 95 percent probability of survival in normal bone. In RA bone, however, the situation is reversed where 86 percent (pegged prosthesis) and 99 percent (keeled prosthesis) of the cement has a greater than 95 percent probability of survival. Bone stresses are shown to be not much affected by the prosthesis design, except at the tip of the central peg or keel. It is concluded that a "pegged" anchorage system is superior for normal bone, whereas a "keeled" anchorage system is superior for RA bone.