Systemic pseudovasculitis from scurvy in anorexia nervosa.
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Adult↗
Biomedical subjects
A J Bridges
Publications and source records attributed to A J Bridges.
Autoantibodies in patients with silicone implants.
We assessed the prevalence of autoantibodies in women with silicone implants and controls. Five hundred consecutive patients with silicone implants, 25 age-matched normal women, 25 women with silicone implants and no rheumatic symptoms, and 100 women with fibromyalgia were tested. Immunofluorescence antinuclear antibodies (ANA) were performed using HEp-2 cells. Subtype autoantibodies were performed by enzyme-linked immunoassay and Western blot. ANA tests were positive in 30% of patients with silicone implants and rheumatic symptoms, 8% of age-matched normal women, 28% of women with silicone implants without clinical symptoms, and 25% of women with fibromyalgia and no silicone implants. The predominant ANA pattern was speckled (55%). ANA subtype testing was positive in 4.8% of patients and none of the controls. We conclude that a larger proportion of women with silicone implants have autoantibodies compared to age-matched asymptomatic women suggesting immune activation in women with silicone implants.
Adult↗
Clinical and laboratory features of patients with scleroderma and silicone implants.
We reviewed the available clinical and laboratory data from 56 patients with scleroderma and silicone implants from the English medical literature and 19 cases which have not been previously reported. The average age of onset of scleroderma was 43.6 +/- 10 years (range 20-73). Patients had silicone implants for an average of 9 +/- 4 years prior to the development of scleroderma (range 1-32). Most patients had limited scleroderma (41%). Twenty three percent had intermediate scleroderma and 36% had diffuse scleroderma. Clinical findings included: Raynaud's phenomenon in 77%, esophageal dysfunction in 53%, and pulmonary involvement in 47%. Cardiac and renal involvement were uncommon. Antinuclear antibodies by immunofluorescence were found in 83 percent of patients. The immunofluorescence pattern was speckled in 53%, centromere in 31% and nucleolar in 9%. Other antibodies (Scl-70, RNP, SSA/Ro, PM-Scl) were found in only a small proportion of patients. A clinical, serologic and immunogenetic comparison of patients with silicone implants and scleroderma and patients with idiopathic scleroderma is needed to better understand the pathogenesis of this disorder.
Adult↗
Structure-activity relationships for 4-anilinoquinazolines as potent inhibitors at the ATP binding site of the epidermal growth factor receptor in vitro.
1. Structure-activity relationships are described for the inhibition of the tyrosine kinase activity (phosphorylation of a fragment of phospholipase Cg1) of the epidermal growth factor receptor (EGFR) by 4-anilinoquinazolines. These compounds are competitive inhibitors at the ATP binding site. 2. The preferred side chain is anilino-, substituted at the 3-position with small lipophilic groups. The quinazoline moiety is absolutely required for activity, but substituents on the quinazoline greatly modulate potency, with electron-donating groups favoured. The most potent analogue, the 6,7-dimethoxy derivative (compound 20), has an IC50 of 29 pmol/L and a very high selectivity for the EGFR over other tyrosine kinase enzymes. 3. The present study shows that it is possible to identify small molecules that are very potent, yet highly selective, inhibitors of a single component of the growth signal transduction pathway in cells.
Adenosine Triphosphate↗
Effectiveness of computer-assisted interactive videodisc instruction in teaching rheumatology to physical and occupational therapy students.
A computer-assisted interactive videodisc instructional program, HP-RHEUM was designed to teach clinical findings in arthritis to occupational and physical therapy students. Using the Rheumatology Image Library videodisc produced by the National Library of Medicine, HP-RHEUM consists of instructional modules which employ advance organizers, examples/nonexamples, summaries, and immediate feedback. To see if HP-RHEUM would be as effective as traditional classroom instruction, control data were collected in 1991 from 52 OT and PT students. Treatment data were collected from 61 students in 1992 when HP-RHEUM entirely replaced lectures. Identical pre- and post-tests consisted of 70 multiple choice questions, with 24 matched to slides. On the slide questions the HP-RHEUM group had significantly higher scores. Otherwise, there was no significant difference in performance between groups. HP-RHEUM provided an independent learning method and enhanced visual comprehension of rheumatologic disease concepts.
Analysis of Variance↗
Tyrosine kinase inhibitors. 7. 7-Amino-4-(phenylamino)- and 7-amino-4-[(phenylmethyl)amino]pyrido[4,3-d]pyrimidines: a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor.
The synthesis of 7-aminopyrido[4,3-d]pyrimidines bearing aromatic side chains at the 4-position is reported. These compounds are shown to be a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Structure-activity relationships (SARs) for substitution in both 4-(phenylamino)- and 4-[(phenylmethyl)amino] side chains were determined, using a series of substituents (NO2, Br, CF3, OMe, NH2, and NMe2) selected primarily for their wide range of electronic properties. In the phenylamino series, 3-substituted derivatives were more potent than the corresponding 2- and 4-substituted analogues. For the 3-substituted compounds, activity was favored by electron withdrawal, in a relationship which could be quantified, with the 3-Br being the most potent compound (IC50 = 0.01 microM compared with IC50 = 0.34 microM for the unsubstituted side chain derivative). No such correlation was apparent for the 2- or 4-substituent, although Br was still the best substituent. In contrast, in the 4-[(phenylmethyl)amino] series, substitution of the side chain was not beneficial. For the 4-(phenylamino) series, the substituent SARs are broadly similar to that found previously for 4-(phenylamino)quinazolines. These results suggest that side chain SARs may be broadly invariant over a range of different chromophores, with the side chain of choice for optimization of EGFR inhibitory activity being 4-[(3-bromophenyl)amino].
Carcinoma, Squamous Cell↗
Tyrosine kinase inhibitors. 5. Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor.
A series of 4-substituted quinazolines and related compounds have been prepared and evaluated for their ability to inhibit the tyrosine kinase activity of the epidermal growth factor receptor on a phospholipase C-gamma 1-derived substrate. The results show a narrow structure-activity relationship (SAR) for the basic ring system, with quinazoline being the preferred chromophore and benzylamino and anilino the preferred side chains. In the 4-anilino series, substitution on the 3-position of the phenyl ring with small lipophilic electron-withdrawing groups provided analogues with enhanced potency. Two series of compounds [4-(phenylmethyl)amino and 4-(3-bromophenyl)amino] were studied to determine SARs for quinazoline substituents. In the more active 4-(3-bromophenyl)amino series, electron-donating groups (NH2, OMe) at the 6- or 7-position increased activity, in a pattern consistent with a requirement for high electron density in the vicinity of the 8-position of the quinazoline ring. The 6,7-dimethoxy derivatives were the most effective in both series, with the 4-(3-bromophenyl)amino derivative (3) having an IC50 of 0.029 nM, making it by far the most potent reported inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor enzyme.
Adenosine Triphosphate↗
A synthetic inhibitor of the mitogen-activated protein kinase cascade.
Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.
3T3 Cells↗
Bullous rash and brown urine in a systemic lupus erythematosus patient treated with hydroxychloroquine.
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Adult↗
Inhibitors of protein tyrosine kinases.
The description in the past year of several novel protein tyrosine kinase inhibitors, which exhibit dramatic improvements in potency and specificity over earlier agents, will be considered a major turning point in the field. These compounds appear to have the necessary pharmacological properties to finally allow clarification of whether suppression of specific tyrosine kinases is of therapeutic benefit in certain disease states.
Animals↗
Enantioselective inhibition of the epidermal growth factor receptor tyrosine kinase by 4-(alpha-phenethylamino)quinazolines.
4-Benzylaminoquinazolines can be potent reversible inhibitors of the EGFR tyrosine kinase at the ATP binding site. Examination of benzylic methylation reveals that an (R)-methyl group is four- to six-fold activating, with an optimal Ki of 630 pM for compound 11. In sharp contrast, (S)-methylation causes a > 30 to 500-fold loss of inhibitory activity, showing that the ATP-binding site of the receptor has very low tolerance for even moderate out-of-plane bulk in certain directions. It is suggested that the best of these inhibitors can induce a conformation of the kinase not available to poorer inhibitors.
Adenosine Triphosphate↗
Rheumatic disorders in patients with silicone implants: a critical review.
More than 1000 patients with rheumatic disorders and silicone implants have been reported. In this review, the clinical features of patients with scleroderma, inflammatory myositis, systemic lupus erythematosus and silicone implants are discussed. The clinical features of the most common rheumatic disorder associated with silicone implants, the "Silicone Implant Associated Syndrome", are introduced. In addition, other local regional, and neurologic disorders associated with silicone implants are discussed. This comprehensive clinical review provides the clinician with information regarding the common symptoms, signs and laboratory features of rheumatic disorders of patients with silicone implants.
Arthritis, Rheumatoid↗
Silicone implant controversy continues.
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Breast Implants↗
A specific inhibitor of the epidermal growth factor receptor tyrosine kinase.
A small molecule called PD 153035 inhibited the epidermal growth factor (EGF) receptor tyrosine kinase with a 5-pM inhibition constant. The inhibitor was specific for the EGF receptor tyrosine kinase and inhibited other purified tyrosine kinases only at micromolar or higher concentrations. PD 153035 rapidly suppressed autophosphorylation of the EGF receptor at low nanomolar concentrations in fibroblasts or in human epidermoid carcinoma cells and selectively blocked EGF-mediated cellular processes including mitogenesis, early gene expression, and oncogenic transformation. PD 153035 demonstrates an increase in potency over that of other tyrosine kinase inhibitors of four to five orders of magnitude for inhibition of isolated EGF receptor tyrosine kinase and three to four orders of magnitude for inhibition of cellular phosphorylation.
3T3 Cells↗
Fibrodysplasia (myositis) ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary connective tissue disorder. Patients with FOP develop progressive ossification of muscle and connective tissue associated with pain and disability. Onset is typically in childhood, and congenital anomalies of the feet are an early sign of this condition. Pain and stiffness of the spine or an inflammatory mass are common presenting features of FOP. Involvement of the spine often leads to complete fusion mimicking ankylosing spondylitis. Studies of twins and families suggest that FOP is a genetically inherited autosomal dominant trait with complete penetrance but variable expressivity. While radionuclide imaging and computed tomography are very sensitive for new bone formation and greatly assist the diagnosis of FOP, unfortunately, effective therapy is unavailable. We present twins with FOP and review the clinical, radiographic, and genetic manifestations of this disorder.
Adult↗
Autoantibodies in patients with silicone implants.
Immune disorders are characterized by development of autoantibodies. Autoantibodies, particularly antinuclear antibodies, are detected in the majority of patients with connective tissue diseases such as systemic lupus erythematosus and scleroderma. Recent reports have described persons with silicone implants who have developed scleroderma and systemic lupus erythematosus. Since autoantibodies are suspected to play an important role in the pathogenesis of the connective tissue disease, the nature of the autoantibodies produced in patients with silicone-associated rheumatic disease is important to understand. A review of the English literature and abstracts from the 1992 American College of Rheumatology meeting showed that immunofluorescent testing for antinuclear antibody was positive in a wide range (7% to 68%) of patients with silicone implants. When examining only those patients with silicone implants and clinical evidence of connective tissue disease, the proportion of patients with a positive immunofluorescent test was less than commonly found in a series of patients with idiopathic connective tissue disease. Sensitive testing by Western blot technique revealed autoantibodies in 10% of patients with silicone implants and negative immunofluorescent test results. Patients with silicone implants and scleroderma-like illness were characterized by anticentromere and anti-PM-Scl antibodies, whereas patients with silicone implants and SLE or undifferentiated connective tissue disease were characterized by antibodies to small nuclear ribonucleoproteins, specifically B'/B polypeptide. In addition, antibodies to a high molecular weight protein have been discovered by Western blot in more than 50% of persons with silicone implants. Differences in autoantibody production between patients with silicone-associated rheumatic disease and patients with idiopathic rheumatic disease may be a distinguishing feature. Further characterization of these autoantibodies is needed.
Antibodies, Antinuclear↗
Subcutaneous cholesterol nodules.
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Aged↗
Silicone breast implants. History, safety, and potential complications.
The purpose of this study is to review the background, safety, and potential complications of silicone breast implants. Relevant studies were identified using a MEDLINE search of the English-language literature, followed by a manual search of the references of all identified articles and a review of abstracts from the 1992 American College of Rheumatology meeting. Review of the literature suggests that silicone does not appear to fulfill the characteristics of an ideal synthetic soft-tissue substitute, although it may be the best substitute available. Silicone breast implants are associated with local inflammation and tissue fibrosis with breast fibrous capsule contracture developing in 10% to 40% of the patients. There are no epidemiologic data that establish a direct link between silicone and cancer or rheumatic disease. However, scleroderma appears to be overrepresented among the published articles on patients with silicone breast implants and rheumatic disease. Autoantibodies of unclear significance may be found in 5% to 30% of women with silicone breast implants. Large, longitudinal, population-based studies that include patients who have had implants for 5 to 15 years may be necessary to fully understand the relationship of silicone implants and immune dysfunction.
Animals↗