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ID PMID Title PublicationDate abstract
8842418 Differential effects of angiostatic steroids and dexamethasone on angiogenesis and cytokin 1996 Aug 1. Subcutaneous implantation of sterile polyether sponges elicited a reproducible neovascular response in rats, as determined by blood flow measurement with a 133Xe clearance technique and confirmed histologically. This model was used to monitor the levels of two cytokines during angiogenesis and to compare the activities of angiostatic steroids and anti-inflammatory steroids. 2. Initial experiments followed the neovascular development over a 20-day period. Daily local injection of hydrocortisone caused a dose-dependent (0.5, 5 and 50 micrograms per sponge) inhibition of the basal sponge-induced angiogenesis. However, daily systemic treatment of hydrocortisone (2, 10 and 50 mg kg-1, s.c.) was less effective at inhibiting angiogenesis, and this inhibition was not sustained by day 20 after sponge implantation. 3. To investigate the involvement of cytokines during the course of angiogenesis, we measured the endogenous levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) in sponge implants. Levels of IL-6 and TNF-alpha peaked at day 7 and day 11 after implantation, respectively. These cytokine levels subsided through the completion of angiogenesis by day 20. 4. Subsequent experiments were carried out over a 14-day period. Among the three angiostatic steroids tested, U-24067 (6 alpha-fluoro-17,21 - dihydroxy-16 alpha-methylpregna -4,9(11)-diene-3,20-dione-21-acetate) showed a dose-dependent inhibition (0.5, 5 and 50 micrograms per sponge per day) of sponge-induced angiogenesis. Tetrahydro-S was also effective at 5 micrograms doses, but medroxyprogesterone failed to affect the angiogenic response. None of these steroids caused atrophies of the spleen and thymus. 5. Daily local injection of dexamethasone (0.5 microgram per sponge) inhibited the basal sponge-induced angiogenesis almost completely. Although higher doses of dexamethasone (5 and 50 micrograms per sponge) did not produce further inhibition of angiogenesis, they caused severe spleen and thymus weight losses, indicative of immunosuppression. 6. At the daily dose of 5 micrograms per sponge, dexamethasone inhibited angiogenesis and produced a marked reduction in the levels of TNF-alpha and IL-6 at day 14. In contrast, hydrocortisone, U-24067 and tetrahydro-S did not influence the levels of TNF-alpha and IL-6. 7. We concluded that the anti-angiogenic activity of angiostatic steroids and anti-inflammatory steroids in the rat sponge model is independent of their ability to reduce the production of TNF-alpha and IL-6. The differential effects of angiostatic and anti-inflammatory steroids suggest that U-24067 and its derivatives may have therapeutic potential in the management of angiogenic diseases such as rheumatoid arthritis.
8629679 Long-term outcome of mothers of children with complete congenital heart block. 1996 Mar OBJECTIVES: To determine the health of mothers of offspring with complete congenital heart block (CHB) both at the time of delivery of the affected child and in the long-term, and the percentage of mothers and children with CHB who had anti-SSA/Ro and/or SSB/La antibodies. PATIENTS AND METHODS: Sixty-four mothers of 64 children with CHB (seen between 1964 and 1993) were identified through the Cardiology database of The Hospital for Sick Children, Toronto, Canada. Medical information from these of children with CHB was evaluated. Data were obtained from the mothers by mailed questionnaire, telephone interview, and/or from the attending physicians. The presence of anti-Ro antibodies and anti-La antibodies were evaluated by ELISA assay. RESULTS: The mean age at the time of delivery of the first child with CHB was 28 +/- 6 years. At the time of delivery 42 (66%) mothers were healthy, 2 (3%) had systemic lupus erythematosus (SLE), 2 (3%) had linear scleroderma, 2 (3%) had rheumatoid arthritis; 3 (5%) had a history of rheumatic fever (but were otherwise well), 1 (2%) had Sjogren's syndrome (SS), and 12 (19%) had an undifferentiated autoimmune syndrome (UAS) (arthralgia, myalgia, photosensitivity, skin vasculitis, Raynaud's phenomenon). The mean time to follow-up from deliver to study was 121 +/- 88 months. The mean maternal age at study was 38 +/- 9 years. Three of 12 mothers who initially had a UAS progressed to SLE (average follow-up time of 80 months, median 96), and 2 developed SS (with average follow-up time 140 months, median 132) and 1 went into remission. The mean follow-up time for the other mothers who did not develop an autoimmune disease was 150 +/- 102 months. Thirty-six of the 42 initially healthy mothers remained well. One mother developed SLE; 1 developed hyperthyroidism; 1 developed anky-losing spondylitis; and 3 developed an UAS. The mean follow-up time of the 36 mothers who remained healthy was similar (123 +/- 97 months) to the 6 initial healthy mothers who developed an autoimmune disease (121 +/- 36 months). Anti-Ro and/or anti-La antibodies were positive in 32 of 53 (60%) mothers tested. Fourteen of the 53 mothers were symptomatic at the time of delivery and 39 were asymptomatic. Anti-Ro and/or anti-La antibodies were positive in 12 of 13 mothers tested at the time of delivery. CONCLUSIONS: The long-term maternal outcome in our cohort was very good as most of the initially healthy mothers remained well at follow-up. Twenty-five percent of the mothers with a UAS and only 2% of the initially healthy mothers developed SLE. The development of an autoimmune disease in an asymptomatic mother identified by the birth of a child with CHB was less common in our study than in previous studies. However, close follow-up of mothers with UAS is warranted.
7485382 Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration i 1995 Nov Oral administration of autoantigens suppresses development of autoimmunity in several animal models, and is being tested in clinical trials in patients with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus at 15 to 20 weeks of age, after mononuclear cell (MNC) infiltration of the pancreatic islets of Langerhans and destruction of insulin-producing beta cells. We have previously shown that oral administration of insulin suppresses insulitis and development of diabetes in the NOD mouse. Oral insulin has no metabolic effect on blood glucose. Oral insulin mediates its effect through a T cell-dependent mechanism as shown by adoptive transfer and T cell depletion experiments, but the mechanisms responsible have not been fully explored. We now report a serial analysis of the cells and cytokines associated with development of diabetes in NOD mice, and contrast this with the findings in animals fed equine insulin or a control protein (ovalbumin). Animals were fed 1 mg twice a week for 5 weeks, beginning at 5 weeks of age. Marked insulitis in naive or ovalbumin-fed NOD mice occurred at 10 weeks, at which time a dense peri-islet and intra-islet MNC infiltration was observed. Immunohistological studies using monoclonal antibodies showed that infiltrating MNC consisted mainly of CD4+ T cells ( > 75% of leukocytes) plus smaller numbers of macrophages and CD8+ T cells. These cells displayed evidence of immune activation with expression of receptors for interleukin-2 (IL-2R) plus Th1 cytokines; dense labeling for IFN-gamma and tumor necrosis factor-alpha, plus lesser amounts of IL-2, was observed. MNC lacked labeling for IL-4, IL-10, prostaglandin-E, or transforming growth factor-beta. By contrast, at 10 weeks, pancreatic tissues from NOD mice fed insulin showed considerably less insulitis, and the residual MNC, although still largely CD4+ T cells plus macrophages, showed dense labeling for IL-4, IL-10, prostaglandin-E, and transforming growth factor-beta and an absence of IL-2, IFN-gamma or tumor necrosis factor-alpha Taken together with our previous findings, these data indicate that oral administration of insulin affects the development of diabetes in NOD mice through the generation of cells that elaborate immunoregulatory cytokines within the target organ and shift the balance from a Th1 to a Th2 pattern of cytokine expression.
7899641 [Arthroplasty of the knee using total condylar prosthesis. Long term results (10 to 17 yea 1994 INTRODUCTION: This study refers to the first 76 Total Condylar knee prostheses that were implanted in 66 patients, with a minimum follow-up of 10 years. MATERIALS AND METHODS: There were 54 women and 12 men with an average age of 65 years (range 45-81). The diagnosis was osteoarthrosis in 63 knees and rheumatoid arthritis in 13. We were able to review 54 prostheses with an average follow-up of 13 years (10-17) using the rating system of the Hospital for Special Surgery and the Survivorship analysis. RESULTS: The results were excellent and good in 72.5 per cent knees and fair and poor in 22 per cent, 3 knees (5.5 per cent) had been revised for deep infection in 2 cases and for aseptic loosening in 1. Pain at rest was absent or mild in all but one patient; walking pain was absent in 32 knees (63 per cent), mild in 12 (23 per cent), moderate in 5 (10 per cent) and severe in 2 (4 per cent). Average range of motion was 89 degrees, ranging from 40 degrees to 120 degrees. A flexion contracture greater 5 degrees was seen in 8 knees (16 per cent). Instability in the frontal plane tested in full extension was more than 5 degrees in 10 patients (19.5 per cent). A significant deterioration of the results occurred in the last 4-5 years, since in 1988 excellent and good results were still 82 per cent. A loss of postoperative alignment of 5 degrees or more was observed in 11 knees: aseptic loosening was identified in 2 of these cases and deformation of the tibial component was seen in 1 knee. In the remaining 8 knees we observed increased lateral instability, compared to the postoperative evaluation. In this group of 8 knees we measured in the AP view the thickness of the tibial component on the lateral and medial side. We found polyethylene wear on the medial side in 4 cases. Ten of the 11 knees with loss of alignment had an early postoperative femoro-tibial axis less than 5 degrees. We observed radiolucent lines in 18 patellar and 27 tibial components. A width greater than 2 mm, correlated to an extension to 5 or more zones, was seen in 3 tibial components with aseptic loosening. Survivorship analysis using aseptic loosening, mechanical failure of the polyethylene and deep infections as end point gave a cumulative success rate at 10 years of 92 per cent% with 95 per cent confidence interval ranging from 85.1 to 98. DISCUSSION: Our study reports a lower percentage of excellent and good results if compared to other series of Total Condylar prosthesis with a comparable follow-up. A significant deterioration of the results occurred in the last years, but this was often not related to the knee itself but to poor general conditions in some patients. In this series there is a relevant number of knees with a post-operative alignment that today we don't consider correct and all the aseptic loosenings occurred in knees with a tibial component positioned in varus. CONCLUSION: Survivorship analysis gave a cumulative success rate comparable with those reported in other studies and confirmed the durability and longevity of this model of prosthesis.
8762983 [Influence of the tibial slope on tibial translation and mobility of non-constrained total 1996 PURPOSE OF THE STUDY: We determined retrospectively the influence of posterior tibial slope and anterior cruciate ligament (ACL) sparing on anterior tibial translation in 68 Cloutier total knee prosthesis. We also precised the influence of posterior tibial slope on knee functional score and appearance of tibial prosthetic interfaces. MATERIAL: 38 Cloutier total knee prosthesis (62 patients mean aged 62 +/- 10 years (36-76) at surgery) reviewed at systematic follow-up control, after a mean period of 5.5 +/- 3 years (2-15), were included in the study. The ACL was preserved in 38 knees and sacrified in 30 knees, the posterior cruciate ligament was preserved in all cases. The prosthetic design was the same whatever the number of cruciate ligament preserved. Osteoarthritis was the reason for surgery in 54 knees, and rheumatoid arthritis in 14 knees. Mean HSS knee score was 54 +/- 10 (29-80) before surgery and 89 +/- 10 (35-100) at follow-up. The mean range of motion was 103 +/- 24 degrees (30-130) before surgery and 110 +/- 14 degrees at follow-up (40-130). METHODS: Anterior tibial translation was determined on two profil x-rays (non weight bearing and weight bearing) at 20 degrees of flexion by comparing the position of tibial tray with regard to posterior edge of femoral prosthesis. Tibial slope was measured on lateral view with regard to peroneus axis. Appearance of tibial prosthetic interface was studied in 48 knees on AP and lateral x-rays orientated with an image intensifier in order to obtain the x-ray would be parallel to the tibial interface. RESULTS: Posterior tibial slope (mean value 6.2 degrees +/- 4.2 degrees) was the main factor influencing the anterior tibial translation (mean value 3.9 +/- 4.6 mm) (p = 0.0007). A 10 degree increase of posterior tibial slope makes the anterior tibial translation rise by 5.6 mm in weight bearing situation. When ACL was preserved, the anterior tibial translation was lower but the decrease was not significant. Likewise, preservation of ACL or the degree of posterior tibial slope had no influence on: 1) HSS knee functional score, 2) range of motion. Radiolucent lines were observed in 18 out of 48 knees, but their occurrence was not influenced by the degree of posterior tibial slope or preservation of ACL. DISCUSSION: Posterior tibial slope has a higher influence than ACL preservation on anterior tibial translation. The increase of posterior tibial slope in order to improve range of motion and to protect the bone-prosthetic tibial interface appeared unjustified with this non-constrained prosthesis. Moreover, implantation of tibial tray (whatever the preservation of ACL) with an important posterior inclination exposes to high anterior tibial translation in weight bearing situation. This last condition could reduce the survivorship of tibial polyethylene.
7890374 Expansion of mycobacterium-reactive gamma delta T cells by a subset of memory helper T cel 1995 Apr Human gamma delta T cells expressing the V gamma 9/V delta 2 T-cell receptor have been previously found to proliferate in response to certain microorganisms and to expand throughout life, presumably because of extrathymic activation by foreign antigens. In vitro expansion of V gamma 9/V delta 2 cells by mycobacteria has been previously shown to be dependent on accessory cells. In order to gain an insight into the mechanisms involved in the expansion of these cells, we have undertaken to identify the peripheral blood subset of cells on which proliferation of V gamma 9/V delta 2 cells in response to mycobacteria is dependent. Contrary to their role in antigen presentation to alpha beta T cells, professional antigen-presenting cells, such as monocytes, B cells, and dendritic cells, were unable to provide the cellular support for the expansion of V gamma 9/V delta 2 cells. Selective depletion of T-cell subsets, as well as the use of highly purified T-cell populations, indicated that the only subset of peripheral blood cells that could expand V gamma 9/V delta 2 cells were CD4+ CD45RO+ CD7- alpha beta T cells. These cells underwent distinct intracellular signaling events after stimulation with the mycobacterial antigen. Expansion of V gamma 9/V delta 2 cells by alpha beta T cells was dependent on cell-cell contact. This is the first evidence that a small subset of the memory helper T-cell population is exclusively responsible for the peripheral expansion of V gamma 9/V delta 2 cells. These data illustrate a unique aspect of antigen recognition by gamma delta T cells and provide new means to study their immune defense role.
8055960 Characterization of ligand binding by the human p55 tumour-necrosis-factor receptor. Invol 1994 Aug 1 Two soluble tumour-necrosis-factor-alpha(TNF)-binding proteins are derived from the extracellular domains of the p55 and p75 TNF receptors. They are considered to play a pivotal regulatory role in TNF-mediated inflammatory processes, including diseases such as rheumatoid arthritis, by competing with the cell surface receptors for TNF and lymphotoxin (LT, tumour-necrosis factor beta). The extracellular domains of the two receptors each contain four similar cysteine-rich repeats of about 40 amino acids, in common with several other cell surface proteins including the p75 nerve-growth-factor receptor and the CD40 and Fas antigens. The aim of this study was to characterize the involvement of the four cysteine-rich repeats of the human p55 TNF receptor in TNF and LT binding by both membrane-bound and soluble forms of the receptor. Individual repeats were systematically deleted by PCR mutagenesis and the variants transiently expressed in COS cells. Immunoprecipitated receptor variants exhibited the expected sizes on SDS/PAGE gels, and bound a panel of conformation-dependent anti-(TNF receptor) antibodies. Binding of TNF by the four soluble derivatives was compared with binding by the wild-type soluble receptor using a TNF-affinity column and a BIAcore Biosensor, by measurement of their ability to inhibit TNF cytotoxicity on WEHI cells, and 125I-TNF binding to U937 cells. delta 4, which lacks the fourth cysteine-rich repeat, bound TNF comparably with the full-length soluble receptor. TNF-binding affinity was unaltered by deletion of the fourth membrane-proximal cysteine-rich repeat, as determined by Scatchard analysis of the transmembrane derivatives. We conclude that the fourth cysteine-rich repeat is not required for TNF binding. In contrast, both the soluble and the transmembrane derivatives lacking any one of the first, second or third repeats failed to bind TNF. Although we cannot entirely exclude the possibility that this may be due to indirect conformational change, rather than the removal of essential epitopes, our results suggest that the first three repeats are each required for TNF binding by both the soluble and the cell-surface receptor.
1605284 The safety of oral contraceptives: epidemiologic insights from the first 30 years. 1992 Jun Because oral contraceptives are used by tens of millions of healthy women, their safety for short-term and long-term use is an important issue that has been examined in a large number of epidemiologic studies. These studies have become more rigorous and have increased in size and analytic sophistication over the years. Although breast cancer remains the most important safety concern, the bulk of recent data suggests that oral contraceptives have no overall impact on a woman's risk of developing this disease. The results are less clear on the risk of cervical cancer and its precursors because of methodologic problems. However, the newer oral contraceptive formulations no longer appear to be associated with an increased risk of myocardial infarction or stroke.
8727894 Bartonella (Rochalimaea) quintana infection in a seronegative hemodialyzed patient. 1996 May Bartonella quintana is a reemerging pathogen responsible for trench fever, endocarditis, bacteremia, and bacillary angiomatosis. We previously reported the first case of a patient with B. quintana-induced chronic adenomegaly, and here we present a report on a second patient. A hemodialyzed patient with Sjögren's syndrome presented with mediastinal adenomegalies and secondary pancytopenia. All diagnostic investigations remained negative, except that a Bartonella-like microorganism was isolated from a bone marrow biopsy. The isolate was identified as B. quintana by a specific mouse polyclonal antibody and by determination of a partial gltA (citrate synthase-encoding) gene and 16S rRNA gene sequences. DNA of the pathogen was also detected in the adenomegaly and in the serum of the patient by PCR amplification of the gltA gene. Anti-B. quintana antibodies were never detected in the patient's serum throughout the 12-month follow-up but were detected in the serum of the patient's cat. The patient's outcome was favorable after treatment with gentamicin. Chronic adenomegaly in seronegative patients is a new clinical entity due to B. quintana.
7687239 Changes of immunoreactivity in alpha 1-antitrypsin in patients with autoimmune diseases. 1993 Jun Recent studies from this laboratory have shown that a monoclonal antibody prepared against a specific epitope on alpha 1-antitrypsin is a valuable diagnostic marker for autoimmune conditions. In the present study we have further characterized this monoclonal antibody and reassessed its diagnostic value in screening samples from patients with various autoimmune conditions. alpha 1-Antitrypsin was micropurified from patients with selected autoimmune conditions and from normal donors. The purified alpha 1-antitrypsin isolated from patients with autoimmune conditions and normal donors was deglycosylated using both a mixture of exoglycosidases and endoglycosidase F. The immunoreactivity of the native and deglycosylated alpha 1-antitrypsin was examined using both a monoclonal antibody and a polyclonal antibody in enzyme linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), respectively. It was noted that alpha 1-antitrypsin isolated from patients with autoimmune diseases generated a displacement curve dissimilar to alpha 1-antitrypsin purified from normal donors or alpha 1-antitrypsin from patients with autoimmune diseases subjected to deglycosylation when these samples were examined by ELISA using the monoclonal antibody. However, when the polyclonal antibody was used for these studies, no difference was found between the native and deglycosylated alpha 1-antitrypsin suggesting that the monoclonal antibody recognized an epitope not detectable by the polyclonal antibody.(ABSTRACT TRUNCATED AT 250 WORDS)
8370186 Characterization of antinuclear autoantibodies present in the serum from nonobese diabetic 1993 Sep The nonobese diabetic (NOD) mouse develops insulin-dependent type 1 diabetes in response to autoantibodies and T-cell attack directed against pancreatic islet cell antigens. Sera obtained from nondiabetic and diabetic female mice demonstrated a 1.4-fold increase in IgG levels when compared to BALB/c control animals. Nondiabetic and diabetic male mice had a 2.1- and 3-fold increase, respectively, in serum IgG levels over that of control mice. Seven of 11 non-diabetic and 7/10 diabetic sera from female NOD mice contained antibody to cytoplasmic or nuclear components of HEp-2 cells. Cytoplasmic staining revealed reaction against cytoskeletal and midbody structures. Punctate nuclear staining patterns with HEp-2 cells showed antibody reaction to the centriole, mitotic chromosomes, and nuclear rim. On the other hand, sera from BALB/c mice were negative for antibody staining of HEp-2 cells. Confirmation of the autoantibody nature of the NOD sera was obtained by antibody staining of nuclear structures from the mouse 3T3 fibroblast cell line, and by staining of salivary gland tissue sections. The nuclear and cytoplasmic staining patterns of diabetic NOD sera were reminiscent of the autoantibody staining patterns observed in Sjögren's syndrome and other inflammatory autoimmune connective tissue diseases.
7902093 Up-regulation by tumor necrosis factor alpha of intercellular adhesion molecule 1 expressi 1993 Nov OBJECTIVE: To examine the regulation of the intercellular adhesion molecule 1 (ICAM-1) gene in cultured human synovial fibroblasts in response to tumor necrosis factor alpha (TNF alpha), and investigate its modulation by the synthetic glucocorticoid, dexamethasone. METHODS: Cell surface expression of ICAM-1 was determined by flow cytometry, enzyme immunoassay, and immunoprecipitation. ICAM-1 messenger RNA (mRNA) levels were monitored by Northern blot. ICAM-1 function was determined by measuring the adhesion of monocytes to synovial fibroblasts. RESULTS: ICAM-1 expression on unstimulated cells was weak but was rapidly enhanced in both a time- and dose-dependent manner following exposure to TNF alpha. Treatment of the cells with TNF alpha also resulted in both a time- and dose-dependent increase in steady-state ICAM-1 mRNA levels, as determined by Northern blot. The increased expression of ICAM-1 was inhibited by cycloheximide and actinomycin D. Cultured synovial fibroblasts from patients with rheumatoid and nonrheumatoid arthropathies responded similarly to TNF alpha. Adhesion studies demonstrated that ICAM-1 is involved in the adherence of peripheral blood monocytes to TNF alpha-activated synovial fibroblasts. In addition, dexamethasone inhibited TNF alpha-induced surface expression of ICAM-1, accumulation of ICAM-1 mRNA, and adhesion of monocytes to TNF alpha-activated synovial fibroblasts. CONCLUSION: These combined results provide further evidence of an important role of ICAM-1 in inflammatory synovitis, as well as a potentially novel site of antiinflammatory action of glucocorticoids.
8664186 Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clini 1995 Sep BACKGROUND: In order to establish the clinico-pathological properties of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma, we evaluated the type, incidence and prognostic significance of clinical and laboratory symptoms. PATIENTS AND METHODS: Sixty-two consecutive patients diagnosed at the Kiel lymph node registry participated in the study. The median patient age was 64 years (range 21-87 years) and the female to male ratio was 1:1.4. Ninety percent of the patients were in stage III and IV and B-symptoms were observed in 68%. At diagnosis patients presented with skin rash (49%), pruritus (32%), edema (38%), pleural effusion (37%), arthritis (18%) and ascites (23%). Furthermore, they exhibited autoimmune phenomena such as cold agglutinines, circulating immune complexes, a positive Coombs test, smooth muscle antibodies, rheumatoid factors, immune hemolysis, a paraprotein, antinuclear antibodies and cryoglobulins. RESULTS: In univariate analysis, survival was significantly related to age (p=0.032), stage (p=0.037), B symptoms (p=0.007), rash/pruritus (p=0.038), edema (p=0.030), ascites (p=0.013), number of clinical symptoms including B symptoms (p=0.004) and excluding B symptoms (p=0.017), lactate dehydrogenase (p=0.007) and hemoglobin (p=0.020). CONCLUSIONS: AILD type T-cell lymphoma characteristically differs from other non-Hodgkin's lymphomas in its clinical signs and laboratory symptoms.
7516663 Clinical toxicity of the interferons. 1994 Feb Since their initial description in 1957, the interferons (IFNs) have been increasingly used to treat a wide array of diseases. Acute adverse effects, i.e. 'flu-like' syndromes, hypo- or hypertension, tachycardia, headache, myalgias and gastrointestinal disorders, occur within the first hour or day after starting treatment. They are seldom treatment-limiting and are easily manageable. Sub-acute and chronic effects develop after several days, usually within 2 and 4 weeks of therapy. The most typical is neurological toxicity, including fatigue/asthenia, and behavioural and cognitive changes. Such symptoms may seriously impair quality of life and result in treatment discontinuation. Seizures have seldom been described. Other infrequent central nervous system adverse effects include vertigo, cramp and oculomotor nerve paralysis. Distal paraesthesias and peripheral neuropathy have been reported. IFN-associated autoimmunity is quite rare but a matter of concern. Biological or clinical manifestations usually require several months to become apparent. Autoantibodies have been shown to develop in most patients but have been inconsistently associated with clinical symptoms of systemic lupus erythematosus, rheumatoid-like arthritis and thyroiditis. Both hypo- and hyperthyroidism have been described but are usually reversible. Other infrequent autoimmune reactions include diabetes, pemphigus and worsening of multiple sclerosis. Although several patients present with a pre-existing autoimmune disorder, no predisposing factor has been clearly established. While hypotension and tachycardia are the most frequent acute cardiovascular complications, a few additional cases of cardiac arrhythmias and myocardial ischaemia have been reported after a short course or several weeks of treatment. These latter complications do not appear to be dose-dependent or age-related. Isolated cases of congestive heart failure have also been described. Mild proteinuria has been observed in 15 to 25% of patients, but acute renal toxicity is uncommon. A transient rise in serum aminotransferase levels is frequently noted during the first stage of therapy, especially in patients receiving the highest dosages. Direct hepatotoxicity is extremely rare. Autoimmune hepatitis, which is ill-diagnosed as chronic viral hepatitis, and de novo induction of autoimmune hepatitis, account for the majority of liver diseases. Haematotoxicity is relatively common but mild to moderate, and develops gradually during the first weeks of treatment. Neutropenia is the most common haematological toxicity, but is usually not dose-limiting and resolves rapidly upon drug discontinuation. Myelosuppression, autoimmune and immune allergic haemolytic anaemias and thrombocytopenias have seldom been described. Cutaneous adverse effects comprised nonspecific erythema and hair loss and, less frequently, vasculitis, local ulcerations at the site of injection and exacerbation of psoriasis.(ABSTRACT TRUNCATED AT 250 WORDS)
8217219 Regulation of macrophage colony-stimulating factor (M-CSF) production in cultured human sy 1993 OBJECTIVE: To study the regulation of macrophage-colony stimulating factor (M-CSF) formation in vitro by human synovial fibroblast-like cells. METHODS: Human synovial cell explant cultures were established using cells from non-rheumatoid donors. M-CSF antigen was measured by immunoassay, and messenger RNA (mRNA) levels were determined by Northern blot. RESULTS: The cytokines, interleukin-1 (IL-1), tumor necrosis factor alpha (TNF alpha), interferon-gamma (IFN-gamma) and IL-4, increased production of M-CSF above constitutive levels. The presence of the cyclooxygenase inhibitor, indomethacin, potentiated the action of IL-1 on M-CSF synthesis, suggesting that an endogenous cyclooxygenase product(s) can down-regulate M-CSF formation. Changes in M-CSF mRNA levels paralleled those in protein levels. The glucocorticoid, dexamethasone, and the retinoid, all-trans retinoic acid, stimulated M-CSF formation. The control of M-CSF synthesis in the synovial fibroblasts differs from that for granulocyte macrophage-CSF (GM-CSF) and granulocyte-CSF (G-CSF). CONCLUSION: These results suggest that cytokine-stimulated synovial fibroblasts may be a source of M-CSF production in the joints of patients with inflammatory arthritis; as a result, monocyte/macrophages may be activated, leading to perpetuation of the inflammation and destructive events occurring in these lesions.
8882622 Differential effects of protein kinase C inhibitors on chemokine production in human synov 1996 Mar 1. Rheumatoid arthritis is associated with the accumulation and activation of selected populations of inflammatory cells within the arthritic joint. One putative signal for this process is the production, by resident cells, of a group of inflammatory mediators known as the chemokines. 2. The chemokines interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1) and RANTES (regulated on activation normal T-cell expressed and presumably secreted) are target-cell specific chemoattractants produced by synovial fibroblasts in response to stimulation with interleukin-1 alpha (IL-1 alpha) or tumour necrosis factor alpha (TNF alpha). The signalling pathways involved in their production are not well defined. We therefore used four different protein kinase C inhibitors to investigate the role of this kinase in the regulation of chemokine mRNA and protein expression in human cultured synovial fibroblasts. 3. The non-selective PKC inhibitor, staurosporine (1-300 nM) significantly increased the production of IL-1 alpha-induced IL-8 mRNA and protein. A specific PKC inhibitor, chelerythrine chloride (0.1-3 microM), also caused a small concentration-dependent increase in IL-8 mRNA and protein production. In contrast, 3-[1-[3-(amidinothio)propyl]-3-indoly]-4-(1-methyl-3-indolyl )- 1H-pyrrole-2,5-dione methanesulphonate (Ro 31-8220) and 2[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3- yl)-maleimide (GF 109203X), two selective PKC inhibitors of the substituted bisindolylmaleimide family had a concentration-dependent biphasic effect on IL-1 alpha or TNF alpha-induced chemokine expression. At low concentrations they caused a stimulation in chemokine production, which was especially evident at the mRNA level. At higher concentrations both inhibited IL-1 alpha or TNF alpha-induced chemokine mRNA and protein production. Ro 31-8220 was 10 fold more potent than GF 109203X, with an IC50 of 1.6 +/- 0.08 microM (mean +/- s.e.mean, n = 4) for IL-1 alpha induced IL-8 production. Ro 31-8220 also inhibited the expression of IL-1 alpha or TNF alpha-induced MCP-1 and RANTES mRNA with a similar potency. 4. The stimulatory effect of staurosporine is discussed in relation to the known poor selectivity of this inhibitor for PKC. It is proposed that activation of an isoform of PKC, possibly PKC epsilon or zeta, which is inhibited by higher concentrations of the bisinodolylmaleimides, plays a role in the regulation of chemokine expression induced by IL-1 alpha or TNF alpha in synovial cells. 5. The inhibition of chemokine production by bisindolylmaleimide compounds heralds a novel approach for future anti-inflammatory therapies.
1384530 Cross-reactive maternal autoantibodies and congenital heart block. 1992 Aug Epitopes with linear sequences recognized by anti-La autoantibodies from seven mothers of children with congenital heart block were recently defined. Eight of these epitopes share sequence identity with three other proteins in addition to the original autoantigen, La. The three proteins are human cardiac myosin beta heavy chain, laminin B1 chain and the M6 protein of Streptococcus pyogenes. Affinity purified anti-La antibodies from a further three mothers bound to the La antigen and also to human cardiac myosin and mouse laminin. Affinity purified antibodies from three mothers of healthy children bound to the La antigen but showed minimal binding to either human cardiac myosin or mouse laminin. Cardiac myosin inhibited the binding of CHB-related anti-La antibodies to both La and myosin. These data support a role for maternal autoantibodies crossing the placenta and recognizing foetal cardiac antigens accessible at a critical developmental stage during gestation. We suggest that this would lead to complement fixation, inflammation and the subsequent pathology associated with congenital heart block.
8874385 A novel in vitro assay for human angiogenesis. 1996 Oct Angiogenesis, the development of new blood vessels, is an important process in tissue development and wound healing but becomes pathologic when associated with solid tumor growth, proliferative retinopathies, and rheumatoid arthritis. To date, there has not been a physiologically relevant in vitro model for human angiogenesis that can be used to screen for enhancers and inhibitors of human angiogenesis and allow further investigation of this process. Initially, culture conditions were established for the induction of human angiogenesis in vitro using fragments of human placental blood vessel. Once the assay was validated, it was examined for its ability to detect known inhibitors and enhancers of angiogenesis. The role of endogenous acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in the angiogenic response was also assessed by performing RT-PCR on both the parent vessel and microvessel outgrowths. In addition, neutralizing antibodies against the three growth factors were used to quantify the relative importance of each growth factor in the angiogenic response. A fragment of human placental blood vessel was embedded in a fibrin gel in microculture plates and was found to give rise to a complex network of microvessels during a period of 7 to 21 days in culture. The response did not require the addition of exogenous growth factors, and thus provides a convenient system for testing substances for their ability to stimulate or inhibit a human in vitro angiogenic response. The ability of the well known angiogenesis antagonist, hydrocortisone, in the presence and absence of heparin, and suramin to significantly inhibit the angiogenic response indicated that the model could be used as an efficient in vitro assay for screening inhibitors of human angiogenesis. The presence of mRNA for aFGF, bFGF, and three isoforms of VEGF, as well as their receptors, FGFR1, FGFR2, Flt-1, and KDR, in vessel outgrowths and the parent vessel, as identified by RT-PCR, strongly implicated aFGF, bFGF, and VEGF as having an important role in this neovascularization response. This was further confirmed by the ability of neutralizing antibodies to aFGF, bFGF, and VEGF to inhibit the angiogenic response to varying extent. Furthermore, the response could be enhanced by the addition of these growth factors in serum-starved cultures. Finally, a stimulatory effect was observed when matrigel was incorporated into the fibrin gel, which indicates that components of the extracellular matrix also play an important role in governing the strength of the angiogenic response. A physiologic angiogenic response relevant to wound healing can be generated by culturing fragments of human placental blood vessels in fibrin gels. The growth factors aFGF, bFGF, and VEGF were shown to play an important role in stimulating this spontaneous angiogenic response. This assay, which can be performed in microcultures, was also shown to be an excellent method for screening for potential inhibitors and enhancers of human angiogenesis.
8040283 Deficient type I protein kinase A isozyme activity in systemic lupus erythematosus T lymph 1994 Jul Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by a dysfunctional cellular immune response. We have previously identified a metabolic disorder of the adenylate cyclase/cAMP/protein kinase A (AC/cAMP/PKA) pathway characterized by impaired cAMP-inducible, PKA-catalyzed protein phosphorylation in intact T lymphocytes from subjects with severe SLE disease activity. Because this metabolic disorder may contribute to abnormal T cell immune effector functions, we tested the hypothesis that impaired PKA-dependent protein phosphorylation is the result of a PKA isozyme deficiency in SLE T lymphocytes. Compared with healthy and rheumatoid arthritis (RA) controls, subjects with severe SLE activity exhibited reduced PKA-catalyzed phosphorylation of proteins in the T lymphocyte plasma membrane where the type I isozyme of PKA (PKA-I) is predominantly localized. Both silver staining and biosynthetic labeling of membrane-associated proteins with [35S]methionine demonstrated that reduced protein phosphorylation was not due to either an altered distribution of or absence of proteins. Moreover, phosphorylation of SLE membrane-associated proteins with the PKA catalytic (C) subunit showed a similar distribution and extent of phosphorylation compared with membrane proteins from healthy T cells, suggesting that SLE T cell membrane proteins could be phosphorylated. Sequential column chromatography of the type I and type II isozymes of PKA (PKA-I, PKA-II) demonstrated a deficiency of PKA-I isozyme activity. Compared with a ratio of PKA-I to PKA-II activity of 4.2:1 in healthy T cells, the activity ratio in T cells from subjects with severe SLE disease activity was 0.99:1 (P = 0.01, SLE versus healthy controls for PKA-I). The deficient PKA-I activity was associated with a significant increase of free C-subunit activity (P = 0.04, SLE versus healthy controls for C-subunit). T cells from subjects with mild/moderate SLE disease activity also exhibited diminished PKA-I activity, yielding a ratio of PKA-I to PKA-II activity of 2.4:1. By contrast, T cells from RA controls possessed increased PKA-I, PKA-II, and free C-subunit activities compared with healthy controls, resulting in a ratio of PKA-I to PKA-II activity of 3.6:1. We conclude that the reduced PKA-catalyzed protein phosphorylation in the plasma membrane of SLE T cells is the result of deficient PKA-I isozyme activity. This is the first identification of a deficiency of PKA activity in SLE T lymphocytes; the deficiency, resulting in diminished protein phosphorylation, may alter cellular homeostasis, contributing to the cellular immune dysfunctions observed in SLE.
7749039 Immune complex specific for the pancreatic duct antigen in patients with idiopathic chroni 1994 Circulating immune complexes (ICs) containing the pancreatic antigen against SP3-1 monoclonal antibody were measured in patients with idiopathic chronic pancreatitis (ICP) and Sjögren syndrome (SjS) by Raji cell and solid-phase radioimmuno-assays (RIA). The mean serum levels of ICs measured by solid-phase RIA were significantly higher in patients with ICP (n = 23) and SjS (n = 21) than control (n = 15, p < 0.05, p < 0.02, respectively). ICs were positive in 10 patients with ICP (43%) and 12 SjS patients (57%). Raji cell assay also revealed a significantly higher serum ICs levels in patients with ICP (n = 17) and SjS (n = 12) compared with those of control (n = 7, p < 0.025, p < 0.005, respectively). Seven patients with ICP (41%) and 8 SjS patients (67%) had positive ICs. This was in contrast to the normal level of ICs in patients with alcoholic chronic pancreatitis, primary biliary cirrhosis, and chronic thyroiditis. Our analysis demonstrated a significant and positive relationship between RIA and Raji cell assay (r = 0.70, p < 0.05). Our results suggest that ICs specific for SP3-1 may play a role in the pathophysiology of ICP and SjS.