Biomedical subjects

C Swearingen

Publications and source records attributed to C Swearingen.

15 recordsLinked to original sources

PubMed2004

Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities.

OBJECTIVE: To analyse patients with rheumatoid arthritis, treated with methotrexate in a weekly academic rheumatology clinic over 13 years, for continuation of courses and reasons for discontinuation. METHODS: All 248 patients with an analysable longitudinal course who took methotrexate in standard care between 1990 and 2003 were studied. Continuation of courses was analysed using life tables. All abnormal and severely abnormal values for aspartate aminotransferase (AST) >40 U/l, >80 U/l, albumin <35 g/l, <30 g/l, white blood cell (WBC) count <4.0 x 10(9)/l, <3.0 x 10(9)/l, and platelet count <150 x 10(9)/l, <100 x 10(9)/l, were identified. Responses of the clinician and subsequent laboratory values were reviewed. RESULTS: Over 1007 person-years, the probability of continuing methotrexate over five years was 79% (95% confidence interval, 72% to 84%). Severe laboratory abnormalities occurred in 2.9 per 100 person-years, specifically 0.9 for AST >80 U/l, 1.1 for albumin <30 g/l, 0.7 for WBC <3.0 x 10(9)/l, and 0.3 for platelets <100 x 10(9)/l. No severe laboratory abnormality progressed to further severity or clinical disease. Permanent discontinuations of methotrexate occurred in 46 patients (19%), 26 (10% of all patients) for adverse effects, 15 (32.6%) for inefficacy; only two discontinuations resulted from laboratory abnormalities, both of WBC, possibly from other sources. CONCLUSIONS: Methotrexate was associated with a high rate of continuation, and few clinically significant laboratory abnormalities. Discontinuation primarily reflected clinical rather than laboratory findings. Vigilance for methotrexate toxicity is required but methotrexate appears among the safest treatments for rheumatoid arthritis.

Antirheumatic Agents↗

PubMed2001

alpha-Amino-beta-sulphone hydroxamates as potent MMP-13 inhibitors that spare MMP-1.

A series of alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-13 and selectivity versus MMP-1. Various substituents were employed on the alpha-amino group (P(1) position), as well as different groups attached to the sulphone group extending into P(1)'. Low nanomolar potency was obtained for MMP-13 with selectivity versus MMP-1 of >1000x for a number of analogues.

Collagenases↗

PubMed2001

alpha-Alkyl-alpha-amino-beta-sulphone hydroxamates as potent MMP inhibitors that spare MMP-1.

A series of alpha-alkyl-alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-2 and MMP-13, and for selectivity versus MMP-1. Low nanomolar potency was obtained with selectivity versus MMP-1 ranging from >10 to >1000. Selected compounds were orally bioavailable.

Alkanes↗

PubMed2000

Preference for nonsteroidal antiinflammatory drugs versus acetaminophen and concomitant use of both types of drugs in patients with osteoarthritis.

OBJECTIVE: To analyze results of treatment of osteoarthritis (OA) with acetaminophen and the nonsteroidal antiinflammatory drugs (NSAID) through a patient survey. METHODS: A 15 minute telephone survey was conducted with 300 patients, including 172 with confirmed OA. RESULTS: Twenty-four percent of patients who took acetaminophen rated it as "very helpful," compared to 31% for ibuprofen, 30% for naproxen, and 56% for diclofenac. Drug continuation beyond 24 months was reported by 33% of patients for acetaminophen, 21% for ibuprofen, 17% for naproxen, and 19% for diclofenac. Acetaminophen was significantly less likely to be discontinued because of toxicity than NSAID. Patients who indicated that they would not take a drug again, and therefore be unlikely to participate in a clinical trial involving this drug, were 26% for acetaminophen, 40% for ibuprofen, 38% for naproxen, and 28% for diclofenac. About 30% of patients who took acetaminophen reported concurrent use of ibuprofen, naproxen, or diclofenac. Among the 67% of patients who identified a drug as "most helpful," 80% named an NSAID, compared to 20% who named acetaminophen or another analgesic as the "most helpful" drug. CONCLUSION: Patients take many different drugs for OA, most of which are not continued beyond 2 years. Many patients take both acetaminophen and an NSAID. Most patients who identified a drug as "most helpful" named an NSAID rather than acetaminophen or an analgesic drug. These findings may be of value in further development of management strategies and guidelines for OA.

Acetaminophen↗

PubMed1999

Toward a multidimensional Health Assessment Questionnaire (MDHAQ): assessment of advanced activities of daily living and psychological status in the patient-friendly health assessment questionnaire format.

OBJECTIVE: To develop components of a multidimensional Health Assessment Questionnaire (MDHAQ) through the addition of new items in the "patient-friendly" HAQ format, including advanced activities of daily living (ADL), designed to overcome "floor effects" of the HAQ and modified HAQ (MHAQ) in which patients may report normal scores although they experience meaningful functional limitations, and psychological items, designed to screen efficiently for psychological distress in routine care. METHODS: The new MDHAQ items, as well as scales for pain, fatigue, helplessness, and global health status on a 2-page questionnaire, were completed by 688 consecutive patients with various rheumatic diseases, including 162 with rheumatoid arthritis (RA), 114 with fibromyalgia, 63 with osteoarthritis, 34 with systemic lupus erythematosus, 20 with vasculitis, 18 with psoriatic arthritis, 16 with scleroderma, and 261 with various other rheumatic diseases, over 2 years at a weekly academic rheumatology clinic. RESULTS: The new MDHAQ items have good test-retest reliability and face validity. MHAQ scores were highest in patients with RA, and scores for other scales were highest in patients with fibromyalgia. On the advanced ADL, 58% of patients reported difficulty with errands, 68% with climbing stairs, 79% with walking two miles, 87% with participating in sports and games, and 94% with running or jogging two miles. On the psychological items, 75% of patients reported difficulty with sleep, 63% with stress, 61% with anxiety, and 57% with depression. Normal MHAQ scores were reported by 23% of patients and normal HAQ scores by 16% of patients who completed these questionnaires, while fewer than 5% had normal scores on the MDHAQ. CONCLUSION: The MDHAQ items overcome in large part the "floor effects" seen on the HAQ and MHAQ, and are useful to screen for problems with sleep, stress, anxiety, and depression in the "patient-friendly" HAQ format. These data support the value of completion of a simple 2-page patient questionnaire by each patient at each visit to a rheumatologist.

Female↗

PubMed1995

Pocket 4 of the HLA-DR(alpha,beta 1*0401) molecule is a major determinant of T cells recognition of peptide.

To investigate the functional roles of individual HLA-DR residues in T cell recognition, transfectants expressing wild-type or mutant DR(alpha,beta 1*0401) molecules with single amino acid substitutions at 14 polymorphic positions of the DR beta 1*0401 chain or 19 positions of the DR alpha chain were used as antigen-presenting cells for five T cell clones specific for the influenza hemagglutinin peptide, HA307-19. Of the six polymorphic positions in the DR beta floor that were examined, mutations at only two positions eliminated T cell recognition: positions 13 (four clones) and 28 (one clone). In contrast, individual mutations at DR beta positions 70, 71, 78, and 86 on the alpha helix eliminated recognition by each of the clones, and mutations at positions 74 and 67 eliminated recognition by four and two clones, respectively. Most of the DR alpha mutations had minimal or no effect on most of the clones, although one clone was very sensitive to changes in the DR alpha chain, with loss of recognition in response to 10 mutants. Mutants that abrogated recognition by all of the clones were assessed for peptide binding, and only the beta 86 mutation drastically decreased peptide binding. Single amino acid substitutions at polymorphic positions in the central part of the DR beta alpha helix disrupted T cell recognition much more frequently than substitutions in the floor, suggesting that DR beta residues on the alpha helix make relatively greater contributions than those in the floor to the ability of the DR(alpha,beta 1*0401) molecule to present HA307-19. The data indicate that DR beta residues 13, 70, 71, 74, and 78, which are located in pocket 4 of the peptide binding site in the crystal structure of the DR1 molecule, exert a major and disproportionate influence on the outcome of T cell recognition, compared with other polymorphic residues.

Amino Acid Sequence↗

PubMed1995

Negatively charged residues interacting with the p4 pocket confer binding specificity to DRB1*0401.

OBJECTIVE: To identify critical residues involved in the binding of a selective peptide to DRB1*0401. METHODS: The binding of peptides to native or site-directed mutant DR molecules was evaluated using enzyme-linked immunosorbent assay and flow cytometry. RESULTS: Amino acid substitutions at DR and peptide residues, which were predicted to contribute to interactions within the DR p4 pocket, had the greatest effects on the specificity of binding. CONCLUSION: Differences in the peptide-binding repertoires of DR molecules may contribute to associations with autoimmune diseases.

Amino Acid Sequence↗

PubMed1994

Individual effects of the DR11-variable beta-chain residues 67, 71, and 86 upon DR(alpha,beta 1*1101)-restricted, peptide-specific T cell proliferation.

The four members of the HLA-DR11 family of class II molecules vary only by three or fewer amino acids via dimorphisms among DR beta-chain residues 67, 71, and 86. However, they differ markedly in their abilities to induce proliferation of DR(alpha,beta 1*1101)-restricted, peptide-specific T cell clones. To dissect which DR11-variable residues, individually and in combination, mediate these functional differences, we used as APC transfectants expressing DR molecules with one of all possible permutations of DR11-variable sequences, including the four DR11 family members, and four additional DR11 variant mutants. The abilities of the wild-type or mutant molecules to present two distinct influenza peptide Ags, HA307-19 and HA128-45, to T cells was assessed in in vitro T cell proliferation assays. Of the naturally dimorphic DR11 positions, residue beta 71 variation significantly influenced the ability of DR11 molecules to present both peptides to DR(alpha,beta 1*1101)-restricted T cells. Residue beta 86 variation had relatively less influence than reported in several other DR and peptide systems. Residue beta 67 variation usually appeared irrelevant to T cell proliferation, but in two mutants led to unexpected T cell proliferation independent of nominal peptide Ag. Peptide binding, assessed by flow cytometry, was not found to be altered by any mutations that disrupted DR(alpha,beta 1*1101)-like presentation. These data indicate that residue beta 71 exerts a central role in influencing the functional differences among DR11 molecules, whereas the widely studied dimorphism of residue beta 86 is not as generally influential in DR11 as in other alleles.

Alleles↗

PubMed1990

The impaired psychiatrist.

Precise data on impaired psychiatrists is lacking, but the evidence suggests significant prevalence due to mental illness, substance abuse, and personality disorder. The complexity and stress of the profession may induce and aggravate vulnerabilities that lead to impaired functioning. Although the very idea of impaired function centers on harmful patient care, colleagues may be affected in ways that, via transference reactions, are not always helpful. There is a great need to balance sanction and rehabilitation, and we need to be proactive and research oriented in dealing with the problem.

Humans↗

PubMed1984