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Biomedical subjects

C Webber

Publications and source records attributed to C Webber.

At least 19 recordsLinked to original sources
PubMed1997

Immunity to cartilage link protein in patients with juvenile rheumatoid arthritis.

OBJECTIVE: To determine whether children with juvenile rheumatoid arthritis (JRA) express cellular immunity to cartilage link protein. METHODS: Link protein was purified from human fetal epiphyseal and bovine adult nasal cartilage. It was used in proliferation assays with the peripheral blood lymphocytes isolated from 54 children with JRA and 22 nonarthritic controls. RESULTS: Patients with JRA expressed a significantly higher prevalence of cellular proliferation to human link protein compared with the control group, independent of whether they had pauciarticular, polyarticular, or systemic disease. In the case of bovine link protein, significant differences were only noted for the polyarticular group. There was significant correlation between the immunity to bovine and to human link proteins. Furthermore, immune responses to both molecules correlated with measures of joint disease activity. CONCLUSION: These results suggest that immunity to link protein may play a role in the pathogenesis of JRA.

Adolescent↗
PubMed1996

Immunity to the G1 globular domain of the cartilage proteoglycan aggrecan can induce inflammatory erosive polyarthritis and spondylitis in BALB/c mice but immunity to G1 is inhibited by covalently bound keratan sulfate in vitro and in vivo.

Earlier work from this laboratory showed that the human proteoglycan aggrecan from fetal cartilages can induce a CD4+ T cell-dependent inflammatory polyarthritis in BALB/c mice when injected after removal of chondroitin sulfate chains. Adult keratan sulfate (KS)-rich aggrecan does not possess this property. We found that two CD4+ T cell hybridomas (TH5 and TH14) isolated from arthritic mice recognize bovine calf aggrecan and the purified G1 domain of this molecule, which also contains a portion of the interglobular domain to which KS is bound. These hybridoma responses to G1 are enhanced by partial removal of KS by the endoglycosidase keratanase or by cyanogen bromide cleavage of core protein. KS removal results in increased cellular uptake by antigen-present cells in vitro. After removal of KS by keratanase, G1 alone can induce a severe erosive polyarthritis and spondylitis in BALB/c mice identifying it as an arthritogenic domain of aggrecan. The presence of KS prevents induction of arthritis presumably as a result of an impaired immune response as observed in vitro. These observations not only identify the arthritogenic properties of G1 but they also point to the importance of glycosylation and proteolysis in determining the arthritogenicity of aggrecan and fragments thereof.

Aggrecans↗
PubMed1996

Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) often develop bone pain, abnormal gait, and unusual fractures while in remission and receiving continuing chemotherapy. A prospective longitudinal cohort study was undertaken of bone mass and biochemical mineral status in 40 consecutive children (27 male, 13 female, aged 0.3-17.0 years) receiving therapy on the Dana-Farber Cancer Institute protocol 87-01. Radiography, lumbar spine dual-photon absorptiometry, and biochemical measurements of mineral status were performed at diagnosis and at 6-month intervals throughout 24 months of chemotherapy. Eleven patients were not completely evaluated (4 deaths and 7 off study). Radiographic evidence of osteopenia was observed in 10, 64, and 76% at diagnosis, 12 and 24 months, respectively. Fractures occurred in 39% of children during treatment. Reduction in bone mineral content (BMC), as measured by Z scores, occurred in 64% of patients and was most severe in those greater than 11 years of age at diagnosis. Reduction in BMC during the first 6 months of therapy had a positive predictive value of 64%, while an increase in BMC had a negative predictive value of 82% for subsequent fracture. By 6 months of therapy, 31/37 (84%) children were hypomagnesemic, of whom 16 (52%) were hypermagnesuric. Plasma osteocalcin was subnormal at diagnosis in 29/40 (73%) but increased to normal by 6 months of treatment. Vitamin D status was normal throughout, but plasma 1,25-dihydroxyvitamin D remained subnormal in greater than 70% of children. Urinary cross-link N-telopeptide was normal at diagnosis and became elevated in 58% of children by the end of therapy. Suppressed bone mineralization is evident at diagnosis in a minority of children with ALL. Skeletal morbidity and a reduction in bone mineral mass become more prevalent during treatment, with increased bone resorption, perhaps mainly as a consequence of corticosteroid administration.

Adolescent↗
PubMed1996

Vitamin D and calcium in the prevention of corticosteroid induced osteoporosis: a 3 year followup.

OBJECTIVE: To determine the efficacy and safety of vitamin D 50,000 units/week and calcium 1,000 mg/day in the prevention of corticosteroid induced osteoporosis. METHODS: A minimized double blind, placebo controlled trial in corticosteroid treated subjects in a tertiary care university affiliated hospital. The sample was 62 subjects with polymyalgia rheumatica, temporal arteritis, asthma, vasculitis, or systemic lupus erythematosus. The primary outcome measure was the percentage change in bone mineral density (BMD) of the lumbar spine in the 2 treatment groups from baseline to 36 mo followup. RESULTS: BMD of the lumbar spine in the vitamin D and calcium treated group decreased by a mean (SD) of 2.6% (4.1%) at 12 mo, 3.7% (4.5%) at 24 mo, and 2.2% (5.8%) at 36 mo. In the placebo group there was a decrease of 4.1% (4.1%) at 12 mo, 3.8% (5.6%) at 24 mo, and 1.5% (8.8%) at 36 mo. The observed differences between groups were not statistically significant. The difference at 36 mo was-0.693% (95% CI -5.34, 3.95). CONCLUSION: Vitamin D and calcium may help prevent the early loss of bone seen in the lumbar spine as measured by densitometry of the lumbar spine. Longterm vitamin D and calcium in those undergoing extended therapy with corticosteroids does not appear to be beneficial.

Adrenal Cortex Hormones↗
PubMed1994

Increased damage to type II collagen in osteoarthritic articular cartilage detected by a new immunoassay.

A new immunoassay was developed to detect denaturation of type II collagen in osteoarthritis (OA). A peptide, alpha 1 (II)-CB11B, located in the CB11 peptide of type II collagen, was synthesized and used to produce a monoclonal antibody (COL2-3/4m) of the IgG1 (kappa) isotype. This reacts with a defined epitope in denatured but not native type II collagen and the alpha 3 chain of type XI collagen. The latter is present in very small amounts (about 1% wt/wt) in cartilage relative to the alpha 1 (II) chain. By using an enzyme-linked immunosorbent assay, type II collagen denaturation and total type II collagen content were determined. The epitope recognized by the antibody was resistant to cleavage by alpha-chymotrypsin and proteinase K which were used to extract alpha 1 (II)-CB11B from the denatured (alpha-chymotrypsin soluble) and residual native (proteinase K soluble) collagen alpha-chains, respectively, present in human femoral articular cartilage. Type II collagen content was significantly reduced from a mean (range) of 14% (9.2-20.8%) of wet weight in 8 normal cartilages to 10.3% (7.4-15.0%) in 16 OA cartilages. This decrease, which may result in part from an increased hydration, was accompanied by an increase in the percent denaturation of type II collagen in OA to 6.0% of total type II collagen compared with 1.1% in normal tissue. The percent denaturation was ordinarily greater in the more superficial zone than in the deep zone of OA cartilage.

Adult↗
PubMed1994

Reproducibility of dual-energy x-ray absorptiometry.

The purpose of this investigation was to determine the short-term reproducibility of measurements of whole-body and subregion bone mass and density, as well as body composition, made by dual energy x-ray absorptiometry. Bone mineral content, bone mineral density and body composition were measured on two occasions, 1 to 2 weeks apart, in 21 women (average age, 20.9 [standard deviation 1.6] years). The method errors of the duplicate measurements, expressed as a percentage of the combined mean values from the two sets of measurements (i.e., as a coefficient of variation), for whole-body bone mineral content, bone mineral density, lean tissue mass and fat mass were 1.6%, 1.1%, 1.4% and 1.8% respectively. The method errors for bone mineral density in the hip were 2.2%, 1.1% and 2.5% for the neck, trochanter and Ward's triangle respectively. On the basis of the method errors and the expected treatment effects, the sample sizes needed for intervention trials (e.g., exercise training) were calculated. All of the whole-body and most of the subregion bone mineral density and lean tissue mass measurements made by dual-energy x-ray absorptiometry were sufficient for detecting the small changes (about 2%) expected in trials with 20 subjects, whereas measurements of subregion bone mineral content and fat mass were less precise.

Absorptiometry, Photon↗
PubMed1993

Benign lymphoepithelial lesions of the parotid.

Persistent generalized lymphadenopathy has been well described in patients with seropositivity to the human immunodeficiency virus (HIV). Moreover, isolated enlargement of the parotid gland and parotid lymphadenopathy have been noted much more frequently over the past few years. Histologically, these lesions demonstrate follicular hyperplasia, cystic dilatation of the ducts lined by pseudo-stratified squamous epithelium, and lymphocytic infiltrates. They are generally considered to be benign lymphoepithelial lesions of the parotid or hyperplastic periparotid lymph nodes. The relationship of this entity to the AIDS-related complex (ARC) and the subsequent development of AIDS is not clear. Over the past 7 years, we have seen 50 patients with parotid enlargement in whom the diagnosis of benign lymphoepithelial lesion was made. Fine-needle aspiration was performed in 32 patients. Although not conclusively diagnostic, needle aspirates ruled out primary salivary glandular pathology. Most patients gave a history of intravenous drug abuse. HIV tests have been performed on a routine basis only in the last 2 years, and these were positive in the majority of the patients. Thirty-five patients underwent surgical excision. In the initial 20 patients, we routinely performed parotid exploration, identification of the facial nerve, and superficial parotidectomy. In the last 15 patients, we changed our surgical approach to parotid exploration and excision of the mass in the tail of the parotid. The exposure of the posterior belly of the digastric muscle, with identification and removal of the deep jugular node, has become routine. In each case, we found an enlarged lymph node in the deep jugular region, which was not clinically palpable preoperatively. The rate of surgical complications was minimal, and, after resection of the mass, patients improved symptomatically. If the patient shows obvious signs of AIDS, a nonsurgical approach with repeated aspirations should be considered, and treatment with zidovudine offered.

AIDS-Related Complex↗
PubMed1992

The induction of arthritis in mice by the cartilage proteoglycan aggrecan: roles of CD4+ and CD8+ T cells.

Peripheral arthritis is produced in BALB/c mice after hyperimmunization with the cartilage proteoglycan aggrecan (PG). Adoptive transfer studies have suggested the roles of T cells including CD8+ T cells in the disease process. To evaluate the roles of CD4+ and CD8+ T cell subsets in vivo in the induction of this disease by immunization, PG-immunized mice were treated with isotype-controlled rat IgG2b monoclonal anti-CD4 or anti-CD8 antibodies, or were left untreated. CD4+ T cell depletion resulted in total inhibition of the disease with markedly decreased anti-PG antibody responses. CD8+ T cell depletion, however, significantly enhanced the severity of the disease without affecting peak anti-PG antibodies, as compared to the control mice. These results demonstrate a crucial role for CD4+ T cells in the pathogenesis of this disease. However, CD8+ T cells do not seem to be required for the induction of arthritis by immunization but instead may play an immunoregulatory role.

Aggrecans↗
PubMed1992

Characterization of proteoglycan-reactive T cell lines and hybridomas from mice with proteoglycan-induced arthritis.

Hyperimmunization with chondroitin sulfate-depleted fetal human cartilage proteoglycan (HFPG) leads to the development of peripheral arthritis and spondylitis in BALB/c mice. Chondroitin-sulfate-depleted adult human cartilage proteoglycan (HAPG) is much less effective at inducing arthritis. These observations suggest age differences in the presence of arthritogenic proteoglycan (PG) epitopes. Earlier studies from this laboratory have indicated an important role for PG-reactive T cells in the pathogenesis of this arthritis model. To investigate further the cellular immunity to PG in mice, two T cell lines, JY.A and JY.D, and two T cell hybridomas, TH5 and TH14, were isolated from mice with PG-induced arthritis and characterized. Two patterns of reactivity to PG emerged from the analysis of these T cells. One pattern, as demonstrated by the T cell line JY.D and the two T cell hybridomas, TH5 and TH14, was characterized by reactivity to HFPG, HAPG, chondroitin sulfate-depleted bovine cartilage PG, the G1 domain (hyaluronate binding region) of bovine cartilage PG and bovine link protein. The epitope(s) recognized by these T cells appear to be part of the homologous regions shared between the G1 domain and the link protein. The second pattern of reactivity, as demonstrated by the T cell line JY.A, was characterized by reactivity to HFPG but not to HAPG or the other PG Ag or bovine link protein. All the T cell lines and hybridomas had a CD4+, CD8- phenotype, possibly belonged to the TH1 subset (IL-2+, IL-4-), and were MHC class II restricted. These studies indicate that HFPG has T cell epitopes in common with HAPG (such as in the G1 domain) and different than those in HAPG. The significance of this data in terms of PG structure, changes with age, and induction of arthritis remains to be established.

Animals↗
PubMed1991

Characterization of aggregating proteoglycans from the proliferative, maturing, hypertrophic, and calcifying zones of the cartilaginous physis.

The introduction of a new microanalytical approach has made it possible to investigate the molecular structure and content of proteoglycans within the extracellular matrix of the physis when the volumes of the matrix and the cells change before mineralization of the extracellular matrix. By using extracts of serial frozen sections with a combination of gel chromatography and chemical, radioimmunoassay, and morphometric analyses, we demonstrated that, in the bovine fetal physis, the content of large aggregating proteoglycans reaches a maximum in the extracellular matrix of the hypertrophic zone, in the region where calcification begins, at the time when calcification starts. Morphometric analyses revealed that, at this time, the volume of matrix is reduced to a minimum. There was no evidence that the remaining proteoglycans were reduced in size, nor was aggregation changed at the time when calcification was initiated. Thus, contrary to earlier reports, there is no indication that these molecules need to be degraded and removed for calcification to begin, although a progressive loss of proteoglycans clearly occurs as the volume of the matrix is reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Heparin effect on bone density.

In order to provide estimates of the risks of symptomatic osteoporosis and reduced bone density in premenopausal women treated with long-term (greater than 1 month) heparin therapy, we evaluated a cohort of 61 consecutive premenopausal women previously treated with long-term heparin (cases) and a group of controls matched for age, parity and duration between the last pregnancy and evaluation. All patients underwent dual photon absorptiometry of the lumbar spine and single photon absorptiometry of the wrist and most cases underwent plain lateral radiography of the thoracolumbar spine in order to exclude silent fractures. Although none of the cases suffered symptomatic fractures (0 of 61, 95% confidence intervals 0.0 to 5.9%), there was a significantly greater proportion of cases than controls with bone density below our pre-defined levels. The long-term implications of our findings are uncertain but because it is possible that the reduction in bone density predisposes women to fractures, this potential risk should be considered when treating women with long-term heparin.

Adult↗
PubMed1990

Needle aspiration biopsy in salivary gland lesions.

The value of needle aspiration biopsy in the evaluation and management of salivary gland pathology is controversial. The major reasons for this controversy are the difficulty in cytologic evaluation and the fact that the extent of surgery can be easily defined based on clinical judgement. However, a preoperative diagnosis is helpful in discussions with patients regarding the extent and type of surgery. Apart from the fact that needle biopsy can distinguish benign from malignant conditions, it is also very useful in distinguishing between salivary and other nonsalivary pathology. Over the past 7 1/2 years, we have performed 160 needle aspirations of parotid, submandibular, and submucosal lesions. Adequate specimens for cytologic evaluation were obtained in 155 patients (97%). A total of 84 parotid lesions, 70 submandibular lumps, and 6 submucosal abnormalities were detected. A cytologic diagnosis of benign pathology was made in 120 patients. Twelve patients had lymphoma and the diagnosis was suspected based on needle aspiration. There were 10 patients with tuberculosis and 30 patients with hyperplastic lymph nodes or benign lymphoepithelial disease of the parotid. There were three false-positive and two false-negative reports. No complications such as hematoma, nerve injury, or infection developed. The major difficulty was in distinguishing between malignancy and obstructive sialadenitis in the submandibular region. Needle aspiration was helpful in evaluating lesions in the tail of the parotid and submandibular area. The cytologic distinction between salivary and nonsalivary pathology was useful in planning the appropriate surgery and the extent of surgical resection. From a clinical standpoint, the distinction between benign and malignant salivary and nonsalivary pathology was very helpful. Preoperative diagnosis of Warthin's tumor, lymphoma, or benign lymphoepithelial disease was essential to the correct management of these patients.

Adolescent↗
PubMed1990

Intraoperative decision making during thyroid surgery based on the results of preoperative needle biopsy and frozen section.

Prognostic factors in well-differentiated thyroid cancer are age of the patient and grade, size, distant metastasis, and extracapsular spread of the disease. However, the surgeon is often not sure about the pathologic diagnosis of thyroid nodules. The accuracy of preoperative studies, such as ultrasonography and thyroid scanning, is limited. The most cost-effective test is fine-needle aspiration, the accuracy of which exceeds 80% in most series. However, a large group of nodules exist for which aspiration cytologic studies are considered to be either suspicious or indeterminate. The decision about the extent of thyroidectomy may be difficult in these patients. Intraoperative frozen section may help the surgeon to distinguish benign from malignant lesions, but as in fine-needle aspiration, the major problem is the distinction between follicular adenoma and follicular carcinoma. The frozen section diagnosis of follicular adenoma was changed to follicular carcinoma in one third of the cases (13 of 38 cases). The decision about the extent of thyroidectomy in patients with follicular adenomas was based on other prognostic factors, such as age and sex of the patient and the size of the nodule. The accuracy of frozen section diagnosis was 95%. Our experience suggests that decisions regarding the extent of thyroidectomy can best be made by preoperative fine-needle aspiration with confirmation by frozen section diagnosis in equivocal cases.

Adenocarcinoma↗
PubMed1989

Studies of a monoclonal antibody to skeletal keratan sulphate. Importance of antibody valency.

A mouse monoclonal antibody (AN9P1) to keratan sulphate is described. In a competitive-inhibition solution-phase radioimmunoassay employing 125I-labelled intact proteoglycan, it reacts preferentially with keratan sulphate bound to the core protein of adult human articular-cartilage proteoglycan and to a much lesser degree with keratan sulphate purified from this proteoglycan. Proteolytic cleavage of the proteoglycan by pepsin and trypsin has little effect on antibody binding, but treatment with papain decreases binding considerably and more than does treatment with keratanase. An even greater decrease in binding is observed after treatment with alkaline borohydride. A comparison of binding of antibody AN9P1 with that of another previously described monoclonal antibody, 1/20/5-D-4, to keratan sulphate [Caterson, Christner & Baker (1983) J. Biol. Chem. 258, 8848-8854] revealed similar binding characteristics, both showing much diminished binding after papain digestion of proteoglycan and even less with purified skeletal keratan sulphate. Removal of the Fc piece of antibody AN9P1 had no significant effect on the differential binding of divalent F(ab')2 fragment to proteoglycan, to papain-digested proteoglycan and to keratan sulphate, although there was a small decrease in binding to papain-digested proteoglycan. Conversion of the antibody into univalent Fab fragment with removal of the Fc piece resulted in diminished binding to proteoglycan, compared with that observed with IgG, and in enhanced binding to free keratan sulphate and to papain-digested proteoglycan. These results suggest that close proximity of keratan sulphate chains on the core protein of proteoglycans favours preferential reactivity of bivalent antibody with these species through cross-bridging of chains by antibody. Conversely, much decreased binding to keratan sulphate on proteoglycan core-protein fragments and to free keratan sulphate results from a lack of close proximity of keratan sulphate. By using univalent Fab fragment in these assays these differences in binding are minimized by preventing cross-bridging and thereby enhancing detection of smaller fragments without sacrificing too much sensitivity of detection of larger proteoglycan species. The persistent preferential binding of Fab fragment to proteoglycan is probably in part the result of the increased epitope density in the intact molecule compared with keratan sulphate in a more disperse form.

Antibodies, Monoclonal↗
PubMed1988

Activation of ras oncogene in aflatoxin-induced rat liver carcinogenesis.

The presence of activated transforming genes was investigated in four primary aflatoxin-induced rat liver tumors in male Fischer rats, in two cell lines generated from such tumors, in an epithelial liver-derived nontransformed cell line, and in the latter cell line after transformation by aflatoxin B1 in vitro. When DNA extracted from these sources was transfected into NIH 3T3 cells, negative results were obtained from focus assays. Cotransfection of these DNA samples with a gene for resistance to G418, followed by selection for resistance to that antibiotic, and tumorigenicity testing in nude mice demonstrated DNA-mediated transfer of the neoplastic phenotype in all cases except for DNA from the nontransformed cell line. DNA extracted from these primary nude mouse tumors used in a secondary round of transfection with NIH 3T3 cells gave positive results in focus assays, which were conserved through succeeding rounds of transfection. By use of appropriate radiolabeled probes, activated ras oncogenes were detected in all samples. N-ras activation was detected in three of the primary rat liver tumors and both hepatoma cell lines. Ki-ras activation was detected in one primary rat liver tumor, and Ha-ras activation was detected in the cell line transformed in vitro with activated aflatoxin B1. The activated Ki-ras oncogene was further characterized by use of synthetic oligonucleotide probes and was shown to contain a G----A transition at the second nucleotide in codon 12.

Aflatoxins↗
PubMed1987

The identification and characterization of two populations of aggregating proteoglycans of high buoyant density isolated from post-natal human articular cartilages of different ages.

After chromatography on Sepharose CL-2B under associative conditions, high-buoyant-density human articular-cartilage proteoglycans were analysed biochemically and by radioimmunoassay with monoclonal antibodies to a core-protein-related epitope and to keratan sulphate. An examination of proteoglycans from individuals of different ages revealed the presence at 1 year of mainly a single polydisperse population containing chondroitin sulphate (uronic acid) and keratan sulphate. From 4 years onwards a smaller keratan sulphate-rich and chondroitin sulphate-deficient population appears in increasing amounts until 15 years. At the same time the larger population shows a progressive decrease in size from 1 year onward. By 23 years and after the proportion of keratan sulphate in the larger chondroitin sulphate-rich proteoglycan increases. Both adult proteoglycan populations are shown immunologically to aggregate with hyaluronic acid, with the smaller showing a greater degree of interaction. The larger population is richer in serine and glycine, and the smaller population contains more glutamic acid/glutamine, alanine, phenylalanine, lysine and arginine; its protein content is also higher. Whether the larger post-natal population represents a different gene product from the single polydisperse population found in the human fetus, which has a different amino acid composition, remains to be established. The smaller population, which represents approximately one-third the mass of the larger population in the adult, may represent a degradation product of the larger population, in which the hyaluronic acid-binding region and keratan sulphate-rich region are conserved.

Aged↗