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R C Williams

Publications and source records attributed to R C Williams.

At least 55 records · Page 3Linked to original sources
PubMed1999

Anti-DNA and anti-nucleosome antibody affinity--a mirror image of lupus nephritis?

OBJECTIVE: To measure relative functional affinities of both IgG anti-DNA and anti-nucleosome antibodies in patients with systemic lupus erythematosus (SLE). METHODS: Serum IgG anti-DNA antibodies were affinity purified from DNA-Sepharose columns (APAD) and tested for functional affinities using dissociation of antigen-antibody binding with diethylamine. IgG antibody affinities for nucleosomes prepared from chicken erythrocyte nuclei and apoptotic normal human leukocyte nuclei were also measured. RESULTS: Many patients with SLE nephritis showed low IgG anti-DNA antibody affinity for both DNA and nucleosomes during clinical phases of active nephritis. Serial studies confirmed an apparent relationship between clinical bouts of active renal disease and low residual serum anti-DNA and sometimes anti-nucleosome affinity. Serial studies of patients with SLE without renal disease did not show episodes of low affinity serum anti-DNA. When APAD were compared to renal biopsy eluates, much higher affinity for DNA was found in renal eluates than in APAD in serum. Similarly, low affinity antibodies in serum were associated with high affinity anti-nucleosome antibody in renal biopsy eluates in some but not all of 10 patients with SLE studied. CONCLUSION: Residual IgG anti-DNA antibody affinity for DNA is often low during phases of active SLE nephritis. When nephritis improves or precipitates chronic renal failure, serum anti-DNA antibody affinity increases. Measurement of anti-DNA antibody affinity may provide a useful indicator of renal disease activity.

Adult↗
PubMed1998

Pharmaceutical development and specification of stereoisomers.

The pharmaceutical development of chiral drugs requires the activities of many different research and development groups. Guidelines which help to coordinate the activities of these groups and assist in the successful development of compounds with either single or multiple chiral centers are outlined and discussed.

Clinical Trials as Topic↗
PubMed1998

The need for acute, subacute and nonacute care at 105 general hospital sites in Ontario. Joint Policy and Planning Committee Non-Acute Hospitalization Project Working Group.

BACKGROUND: Previous studies of hospital utilization have not taken into account the use of acute care beds for subacute care. The authors determined the proportion of patients who required acute, subacute and nonacute care on admission and during their hospital stay in general hospitals in Ontario. From this analysis, they identified areas where the efficiency of care delivery might be improved. METHODS: Ninety-eight of 189 acute care hospitals in Ontario, at 105 sites, participated in a review that used explicit criteria for rating acuity developed by Inter-Qual Inc., Marlborough, Mass. The records of 13,242 patients who were discharged over a 9-month period in 1995 after hospital care for 1 of 8 high-volume, high-variability diagnoses or procedures were randomly selected for review. Patients were categorized on the basis of the level of care (acute, subacute or nonacute) they required on admission and during subsequent days of hospital care. RESULTS: Of all admissions, 62.2% were acute, 19.7% subacute and 18.1% nonacute. The patients most likely to require acute care on admission were those with acute myocardial infarction (96.2% of 1826 patients) or cerebrovascular accident (84.0% of 1596 patients) and those admitted for elective surgery on the day of their procedure (73.4% of 3993 patients). However, 41.1% of patients awaiting hip or knee replacement were admitted the day before surgery so did not require acute care on admission. The proportion of patients who required acute care on admission and during the subsequent hospital stay declined with age; the proportion of patients needing nonacute care did not vary with age. After admission, acute care was needed on 27.5% of subsequent days, subacute care on 40.2% and nonacute care on 32.3%. The need for acute care on admission was a predictor of need for acute care during subsequent hospital stay among patients with medical conditions. The proportion of patients requiring subacute care during the subsequent hospital stay increased with age, decreased with the number of inpatient beds in each hospital and was highest among patients with congestive heart failure, chronic obstructive pulmonary disease and pneumonia. INTERPRETATION: In 1995, inpatients requiring subacute care accounted for a substantial proportion of nonacute care days in Ontario's general hospitals. These findings suggest a need to evaluate the efficiencies that might be achieved by introducing a subacute category of care into the Canadian health care system. Generally, efforts are needed to reduce the proportion of admissions for nonacute care and of in-hospital days for other than acute care.

Acute Disease↗
PubMed1998

Genetic admixture and gallbladder disease in Mexican Americans.

Gallbladder disease is a common source of morbidity in the Mexican American population. Genetic heritage has been proposed as a possible contributor, but evidence for this is limited. Because gallbladder disease has been associated with Native American heritage, genetic admixture may serve as a useful proxy for genetic susceptibility to the disease in epidemiologic studies. The objective of our study was to examine the possibility that gallbladder disease is associated with greater Native American admixture in Mexican Americans. This study used data from the Hispanic Health and Nutrition Examination Survey and was based on 1,145 Mexican Americans who underwent gallbladder ultrasonography and provided usable phenotypic information. We used the GM and KM immunoglobulin antigen system to generate estimates of admixture proportions and compared these for individuals with and without gallbladder disease. Overall, the proportionate genetic contributions from European, Native American, and African ancestries in our sample were 0.575, 0.390, and 0.035, respectively. Admixture proportions did not differ between cases and noncases: Estimates of Native American admixture for the two groups were 0.359 and 0.396, respectively, but confidence intervals for estimates overlapped. This study found no evidence for the hypothesis that greater Native American admixture proportion is associated with higher prevalence of gallbladder disease in Mexican Americans. Reasons for the finding that Native American admixture proportions did not differ between cases and noncases are discussed. Improving our understanding of the measurement, use, and limitations of genetic admixture may increase its usefulness as an epidemiologic tool as well as its potential for contributing to our understanding of disease distributions across populations.

Adult↗
PubMed1998

Determination of primary amino acid sequence and unique three-dimensional structure of WGH1, a monoclonal human IgM antibody with anti-PR3 specificity.

Transformed B cells making monoclonal IgM-lambda anti-PR3 antibody WGH1 from a patient with Wegener's granulomatosis were used to prepare mRNA and synthesize cDNA. PCR primers for human micro and lambda chains were then employed to amplify heavy- and light-chain V-regions followed by cloning into pCR2-1 vector and sequencing. Molecular modeling of VH regions employed knowledge-based homology modeling to obtain minimum energy conformation. The VH sequence was subgroup III with marked overall homology to VH1.9III. The VHCDR3 region of WGH1 was unique, consisting of 21 amino acid residues which included seven tyrosines as well as three negatively charged aspartic acid residues. The VL region was subgroup II with a negatively charged glutamic acid at position 100 in CDR3. Molecular modeling of VH revealed a major conformational difference in the shape of CDR3 compared with other antibodies for which three-dimensional structures have been determined. Monoclonal antibody WGH1 reacting with PR3 (a highly positively charged molecule) shows a unique reactive cassette within VHCDR3 with a number of negatively charged aspartic acid residues. WGH1 VHCDR3 contains a loop which shows a major projection not usually recorded in other previously studied antibody molecules.

Amino Acid Sequence↗
PubMed1998

Urinary loss of immunoglobulin G anti-F(ab)2 and anti-DNA antibody in systemic lupus erythematosus nephritis.

The objective of this study was to determine whether the low levels of serum immunoglobulin G (IgG) anti-F(ab)2 seen in some patients with active systemic lupus erythematosus (SLE) were directly related to the deposition of antibody with this specificity in the kidney or alternatively to the urinary loss of IgG anti-F(ab)2. Serum Levels of IgG anti-F(ab)2, anti-tetanus toxoid, and anti-ds DNA antibody were measured in parallel with urinary excretion of these same 3 antibodies in 28 patients with SLE nephritis and in 28 control patients with other forms of chronic kidney disease. Low levels of both serum IgG anti-F(ab)2 or anti-tetanus antibody appeared to correlate with increased levels of urinary loss of these same antibodies in some patients with SLE and in control subjects with kidney disease. However, urinary loss could not account for low serum levels of either IgG antibody in many subjects. Quantitative 24-hour urinary losses of IgG anti-F(ab)2 and anti-DNA were much higher in patients with SLE than in control subjects with kidney disease (P < .05), whereas amounts of IgG urinary loss of anti-tetanus were similar in patients with SLE and in control subjects. In nearly 1 third of SLE nephritis patients, 13% to 53% of total excreted urinary IgG showed anti-DNA enzyme-linked-immunosorbent assay reactivity. Urinary IgG in many patients with SLE showed both anti-DNA and anti-F(ab)2 reactivity, but dual anti-DNA/F(ab)2 specificity was more pronounced in affinity-isolated serum IgG anti-DNA or anti-F(ab)2 than in excreted urinary IgG molecules. The affinity of urinary IgG for either DNA or F(ab)2 was much lower than the same antibody activities measured either in serum or in kidney biopsy eluates. When the relative affinity of anti-DNA antibody in serum, urine, and kidney biopsy eluate was measured in parallel, the highest affinity antibody was found in kidney biopsy eluates, followed by serum antibody with urine antibody affinity showing the lowest values. These findings suggest a relative concentration of the highest affinity, doubly reactive IgG anti-DNA/F(ab)2 in SLE kidney tissues during SLE nephritis and implicate this process as an important factor in ongoing tissue damage.

Adolescent↗
PubMed1998

Local delivery of chemotherapeutic agents in periodontal therapy: has its time arrived?

The concept of locally delivering chemotherapeutic agents to the periodontal pocket as a method to treat periodontal disease has been studied for over 20 years. A number of locally delivered chemotherapeutic agents in periodontal therapy are either currently available or under investigation. Clinical efficacy derives from sustained-release technology to maintain an effective concentration of drug within the periodontal pocket for a clinically relevant length of time. Studied drugs have mainly been antimicrobials, both antibiotics and antiseptics. Most agents have been tested as adjuncts to scaling and root planing; a few have been studied as stand-alone monotherapies. Collectively, the data indicate that the use of locally delivered antimicrobials as adjuncts results in a significant increase in the reduction of probing depth compared with scaling and root planing alone. In other trials, results in reducing probing depth following the use of stand-alone locally delivered antimicrobials have been equivalent to those of scaling and root planing over a specified time. This Symposium was organized to present the current state-of-the-art with regard to the use of locally delivered antimicrobials in the treatment of periodontal disease. 5 experts in the field who have had considerable experience in studying locally delivered antimicrobials presented data. These speakers reviewed the clinical findings regarding efficacy of 5 different antimicrobial agents. An ensuing panel discussion was to consider treatment recommendations for locally delivered antimicrobials.

Administration, Topical↗
PubMed1998

Modulation of the host response in the treatment of periodontitis.

Periodontitis has two distinct but interconnected etiologic components: periodontopathic bacteria adjacent to the periodontal tissues, and host-mediated connective tissue-destructive responses to the specific causative bacteria and their metabolic products. Although past and existing therapies have focused primarily on the causative microbial challenge, the host component of periodontal destruction has recently been intensely studied. New treatment strategies that focus on attenuating destructive host responses are emerging. Host modulatory agents, when used adjunctively, may enhance clinical therapeutic responses and make these responses more predictable in the susceptible host. The ongoing development of safe, effective pharmacotherapies that specifically target host response mechanisms, and the introduction of such pharmacotherapies as adjuncts to traditional, antimicrobial interventions may represent a new, integrated approach in the long-term treatment and management of this chronic disease.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Wegener's look-alike.

We describe a 75-year-old woman with a maxillary sinus mass who was evaluated for Wegener's granulomatosis (WG). After further examination, she was diagnosed with plasma cell granuloma. This benign tumor should be noted as a look-alike for WG.

Aged↗
PubMed1998

Rupture of a hepatic artery aneurysm and renal infarction: 2 complications of fibromuscular dysplasia that mimic vasculitis.

Fibromuscular dysplasia (FMD) is one of the most important mimics of vasculitis. FMD is more prevalent in women and may cause infarcts of organ systems including the brain, intestines, and extremities. These acute clinical presentations often raise the suspicion of vasculitis and therefore rheumatologists will be asked to evaluate these patients. One of the frequent manifestations of FMD is renal artery involvement. Angiographic evaluation often shows a "string of beads" appearance of the renal arteries but sometimes only tapering of the vascular lumen or cutoffs may be seen. In contrast, hepatic artery involvement with FMD occurs much less frequently and may initially present with life threatening intraabdominal bleeding. Celiac angiograms of these patients often show aneurysms, a presentation similar to vasculitis. Only a high level of suspicion for FMD and careful evaluation of clinical facts will lead to correct diagnosis. This will prevent the wrong diagnosis of vasculitis and subsequent treatment with potentially toxic medications. We present 2 cases of FMD involving the renal and hepatic arteries that illustrate this diagnostic challenge.

Adult↗
PubMed1997

Cytoplasmic chaperonin containing TCP-1: structural and functional characterization.

Actin and tubulin polypeptide chains acquire their native conformation in the presence of the cytoplasmic chaperonin containing TCP-1 (CCT, also called TRiC) and, in the case of alpha- and beta-tubulin, additional protein cofactors. It has been previously demonstrated that nucleotide exchange and ATP hydrolysis act to switch CCT between conformations that interact either strongly or weakly with unfolded substrates [Melki, R., & Cowan, N.J. (1994) Mol. Cell. Biol. 14, 2895-2904]. The present study further documents the conformational changes and function of CCT. It is first shown, by the use of a range of labeled denatured substrate proteins and a radiolabeled total soluble HeLa cell extract, that CCT in the absence of nucleotides can bind any of a large number of proteins in vitro with high affinity. Second, by the use of denatured labeled beta-actin and beta-tubulin as model substrates for binding to CCT, we demonstrate that the CCT particle can contain two substrate protein chains simultaneously. Third, by electron microscopy, sedimentation velocity, and intrinsic fluorescence measurements, we document the conformational difference between CCT in its ATP- and ADP-bound forms, as well as the change that results from binding of substrate protein. A model summarizes substrate association with CCT and the role of the nucleotide in regulating the affinity of CCT for target proteins.

Actins↗
PubMed1997

Cross-reactivity of human IgG anti-F(ab')2 antibody with DNA and other nuclear antigens.

OBJECTIVE: To characterize immunologic specificity and possible antiidiotype activity of IgG anti-F(ab')2 in normal subjects as well as in patients with active and inactive systemic lupus erythematosus (SLE). METHODS: IgG anti-F(ab')2 and anti-double-stranded DNA (anti-dsDNA) were affinity isolated from immunoadsorption columns of F(ab')2 and dsDNA linked to Sepharose 4B. Affinity-purified IgG anti-F(ab')2 (APAF) and affinity-isolated IgG anti-dsDNA (APAD) were tested by enzyme-linked immunosorbent assay (ELISA) for other cross-reacting specificities including anti-Sm, anti-Sm/RNP, and anti- Crithidia binding. Anti-DNA specificity of APAF and APAD was assayed by S1 nuclease treatment of heat-denatured DNA. Rabbit antiidiotypic antisera were prepared by immunization with APAF and APAD from normal subjects and SLE patients and absorption with insolubilized human Cohn fraction II (Fr II). VL and VH regions of 5 monoclonal IgM antibodies with anti-F(ab')2/anti-DNA specificity generated by Epstein-Barr virus B cell stimulation were sequenced by polymerase chain reaction and characterized for VH and VL subgroup. APAF and APAD were also examined by high-resolution electron microscopy for possible ring forms indicative of antiidiotypic V-region interactions. RESULTS: APAF from normal subjects, representing 0.08-0.18% of serum IgG, showed striking relative concentrations of both anti-F(ab')2 and anti-DNA, as well as anti-Sm and anti-Sm/RNP ELISA reactivity. Both APAF and APAD reacting with F(ab')2 or dsDNA on the ELISA plate could be cross-inhibited by F(ab')2 or DNA in solution. Anti-DNA reactivity in normal APAF and APAD was much more sensitive to S1 nuclease treatment than similar fractions from SLE patients. Neither APAF nor APAD from controls produced positive antinuclear immunofluorescence or positive Crithidia staining, whereas these were strongly positive using SLE APAF and APAD. Absorbed rabbit antisera against normal or SLE APAF and APAD showed strong ELISA reactivity against both APAF and APAD, but no residual reactivity with normal Fr II. VL and VH sequencing of monoclonal human IgM antibodies showing both anti-F(ab')2 and anti-DNA reactivity showed relative VH3, V kappa 1 or VH1, V kappa 3 restriction. No evidence of ring forms or V-region "kissing" dimers was obtained when normal or SLE APAD or APAF was examined by high-resolution electron microscopy. CONCLUSION: IgG anti-F(ab')2 in both normal subjects and SLE patients represents a polyreactive Ig subfraction with concomitant anti-DNA, anti-Sm, and anti-Sm/RNP specificities. Anti-DNA reactivity in SLE is qualitatively different from that in normal APAD and APAF since normal APAD and APAF anti-DNA is much more sensitive to S1 nuclease digestion of denatured dsDNA. APAF and APAD share distinct V-region antigens which may be related to prominent VH3 or VH1 antigenic components. No evidence for in vivo complexing of anti-DNA and anti-F(ab')2 as ring forms or antiidiotype-IgG complexes was observed during ultrastructural studies. In both normal individuals and SLE patients, APAF may represent a small polyreactive IgG subfraction which also contains antinuclear and anti-DNA specificities.

Adolescent↗
PubMed1997

Affinity columns containing anti-DNA Id+ human myeloma proteins adsorb human epibodies from intravenous gamma globulin.

OBJECTIVE: To study eluates of intravenous gamma globulin (IVGG) prepared from affinity columns of human cationic IgG myeloma proteins bearing anti-DNA idiotype (Id) markers 16/6, F4, 3I, and 8.12 for possible anti-Id (combining site) blocking activity. METHODS: Anti-DNA idiotypic antibody activity was studied in 3 preparations of IVGG containing high, medium, and low levels of IgG anti-F(ab')2, and in 4 other commercial IVGG preparations. Affinity-purified IgG anti-DNA (APAD) from systemic lupus erythematosus (SLE) patients was biotinylated, and binding to DNA coated on enzyme-linked immunosorbent assay plates was used to measure anti-DNA antibody activity. IVGG was adsorbed to Sepharose 4B affinity columns linked to a panel of cationic human IgG myeloma proteins positive for anti-DNA Id markers 16/6, F4, 3I, and 8.12. Material adsorbing to such columns was eluted at low pH (2.5) and after neutralization, tested for its ability to inhibit biotinylated APAD reacting with DNA. RESULTS: Only 0.05-0.9% of IVGGs bound firmly to Id affinity columns. These IVGGs were then eluted, using pH 2.5 glycine-saline and eluates neutralized to pH 7.4. Column flowthrough and eluate fractions were compared for their ability to block SLE APAD reacting with DNA. Significant inhibition of SLE APAD combining sites was observed with eluates from anti-DNA Id affinity columns; however, no correlation between IVGG anti-F(ab')2 activity and true anti-Id blocking of APAD was apparent. No residual anti-Id activity remained in column flowthrough fractions. No anti-Id blocking activity was recorded for IVGG eluates from human cationic myeloma columns devoid of the 4 anti-DNA Id markers. DNase treatment of IVGG or Id column eluates did not affect anti-Id blocking activity. Thus, all detectable anti-DNA idiotypic antibody capable of blocking SLE anti-DNA combining sites bound to Id+ affinity columns. Column eluates also showed some relative concentration of IgG anti-DNA activity, which was of lower affinity for DNA than antibodies also present in eluates which blocked anti-DNA combining sites. CONCLUSION: The presence of both anti-DNA and antiidiotypic (anti-combining site) activity in human anti-DNA Id column eluates indicates that epibodies from IVGG are relatively concentrated when this strategy is used. This approach may lead to a new strategy for treatment of SLE nephritis.

Adsorption↗
PubMed1997

Antigenic determinants reacting with rheumatoid factor: epitopes with different primary sequences share similar conformation.

Polyclonal or monoclonal human IgM rheumatoid factors (RF) react with eight antigenic sites on the CH3 IgG domain, four sites on CH2 and two on human beta 2-microglobulin. All 14 of these RF-reactive epitopes are linear 7-11 amino acid peptides with different primary sequence. We questioned whether RF reactivity with such a variety of epitopes showing no obvious sequence homology might result from conformational similarities shared by various RF-reactive regions. Strong support for this concept was obtained using rabbit antisera as well as mouse mAbs to individual CH3, CH2 or beta 2m RF-reactive peptides. Major cross-reactivity was demonstrated between most of the 14 different CH3, CH2, or beta 2m RF-reactive peptides using individual anti-epitope antibodies. Molecular modelling studies of these peptides showed striking similarities in three-dimensional shape among many RF-reactive peptides. Main-chain atoms rather than side chains seemed to contribute most directly to conformational similarity. Molecular simulation studies on control peptides showed no conformational similarities with RF-reactive peptides. Our studies indicate that autoantibodies such as RF recognize main-chain conformations of reactive epitopes and react with a number of antigenic determinants of quite different primary sequence but similar main chain conformations.

Amino Acid Sequence↗
PubMed1997

Interactions of HLA-B*4801 with peptide and CD8.

Functional properties of the B*4801 allotype were investigated using HLA class I-deficient 221 cells transfected with B*4801 cDNA. From pool sequence analysis of endogenously bound peptides, B*4801 was shown to select for nonamer peptides having glutamine or lysine at position 2 and leucine at the carboxyl-terminus. In an in vitro cell-cell binding assay, B*4801 binds CD8 alpha homodimers weakly due to the presence of a threonine residue at position 245 in the alpha 3 domain. A mutant B*4801 molecule in which alanine replaces threonine 245, binds CD8 alpha homodimers at levels comparable to those of other HLA class I allotypes. Despite the low affinity of B*4801 for CD8 alpha, alloreactive T-cells that recognize B*4801 molecules expressed by the 221 transfectant are inhibited by anti-CD8 monoclonal antibodies. Analysis of 25 B*48-expressing individuals from various populations showed threonine 245 was encoded by every B*48 allele.

Alleles↗
PubMed1997

Enantiospecific inhibition of ligature-induced periodontitis in beagles with topical (S)-ketoprofen.

Systemic and topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce periodontal disease progression in both animal models and human subjects. Our present research focuses on single enantiomers of these agents to examine whether enantiospecific therapy will be efficacious in slowing periodontitis. The purpose of this study was to evaluate the inhibitory effects of (S)-ketoprofen on experimentally induced alveolar bone loss in beagle dogs. 16, 18-month-old, female beagles were brought to optimal periodontal health over a 2-week pretreatment period. Experimental periodontitis was then induced by placing silk ligatures around premolar and molar teeth and by instituting a soft, plaque-promoting diet. At baseline, animals were randomized to 1 of 4 groups, consisting of 2x daily administration of (1) placebo dentifrice, (2) 0.3% (S)-ketoprofen dentifrice, (3) 3.0% (S)-ketoprofen dentifrice, or (4) 10.0 mg (S)-ketoprofen capsules (p.o.) over a 60 day treatment period. Standardized, periapical radiographs exposed at days 1 and 60 were analyzed by computer-assisted digital radiography in order to assess the rate of alveolar bone loss. Secondary outcomes included technetium 99m-tin-diphosphonate (99mTc-Sn-MDP) uptake and the gingival index. At baseline, no differences were observed among the groups for linear bone height or 99mTc-Sn-MDP uptake ratios. From days 1 to 60, cohorts differed significantly in terms of bone loss rates (p < 0.001). In particular, beagles treated with systemic or topical (S)-ketoprofen (0.3% or 3.0% dentifrices) exhibited significantly lower mean rates of bone loss compared to placebo treated beagles (p < 0.05). Group differences in mean radiopharmaceutical uptake ratio changes approached significance (ANOVA, p = 0.07), where animals treated with topical 0.3% (S)-ketoprofen demonstrated a reduction and other groups demonstrated elevations over the 60-day dosing period. Treatment cohorts did differ significantly with respect to changes in mean gingival indices (p < 0.05). Animals treated with 0.3% or 3.0% (S)-ketoprofen dentifrice exhibited significantly reduced elevations in gingival index scores as compared to placebo treated animals. These data provide evidence that enantiospecific therapy with (S)-ketoprofen, topically or systemically delivered, may alter the progression of periodontal disease in the beagle dog model.

Alveolar Bone Loss↗