Search PubMed⌕ Search

Biomedical subjects

J Warner

Publications and source records attributed to J Warner.

At least 55 records · Page 3Linked to original sources
PubMed2001

Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alpha-converting enzyme and matrix metalloproteinases.

Tumor necrosis factor-alpha (TNF)-converting enzyme (TACE) cleaves the precursor form of TNF, allowing the mature form to be secreted into the extracellular space. GW3333, a dual inhibitor of TACE and matrix metalloproteinases (MMPs), was compared with an anti-TNF antibody to evaluate the importance of soluble TNF and MMPs in rat models of arthritis. Oral administration of GW3333 completely blocked increases in plasma TNF after LPS for up to 12 h. In a model wherein intrapleural zymosan injection causes an increase in TNF in the pleural cavity, GW3333 completely inhibited the increase in TNF in the pleural cavity for 12 h. Under these dosing conditions, the plasma levels of unbound GW3333 were at least 50-fold above the IC(50) values for inhibition of individual MMPs in vitro. In a model wherein bacterial peptidoglycan polysaccharide polymers reactivate a local arthritis response in the ankle, a neutralizing anti-TNF antibody completely blocked the ankle swelling over the 3-day reactivation period. GW3333 administered b.i.d. over the same period also inhibited ankle swelling, with the highest dose of 80 mg/kg being slightly less active than the anti-TNF antibody. In a 21-day adjuvant arthritis model, the anti-TNF antibody did not inhibit the ankle swelling or the joint destruction, as assessed by histology or radiology. GW3333, however, showed inhibition of both ankle swelling and joint destruction. In conclusion, GW3333 is the first inhibitor with sufficient duration of action to chronically inhibit TACE and MMPs in the rat. The efficacy of GW3333 suggests that dual inhibitors of TACE and matrix metalloproteinases may prove therapeutic as antiarthritics.

ADAM Proteins↗
PubMed2000

Asthma--the changing face of drug therapy.

Until the recent introduction of long acting beta 2-agonists and the leukotriene antagonists, the drug treatment of asthma had remained largely unchanged for a quarter century. Recent studies have demonstrated the efficacy of the long acting beta 2-agonists in the management of asthma in children and highlighted their value as an adjunct to inhaled corticosteroids. The leukotriene antagonists are an important new class of drug therapy which target a specific area of asthma pathogenesis. Whilst they have been shown to be effective for asthma, their exact role in the clinical situation remains to be established. Recent guidelines have emphasised the important role of inflammation in persistent asthma and recommended the early institution of anti-inflammatory treatment. Many patients remain uncontrolled despite high doses of anti-inflammatory agents including oral corticosteroids. Recent experience with other immunomodulatory agents such as cyclosporin, methotrexate and intravenous immunoglobulin has highlighed their potential as steroid sparing agents. With improved understanding of asthma pathogenesis the potential for specific targeted therapies has become evident. Monoclonal antibodies to IgE and certain cytokines are being investigated as possible treatments for asthma. Similarly, preliminary studies of selective phosphodiesterase inhibitors in asthmatic individuals have been encouraging. Other potential therapies include platelet-activating factor receptor antagonists, tryptase inhibitors and prostaglandin E analogs. The continued development of such targeted treatments should ensure a greater diversity of therapeutic options for the management of asthma in the new millennium.

Adrenergic beta-Agonists↗
PubMed2000

A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns.

BACKGROUND: Onychomycosis, a fungal infection of the nail bed, is responsible for up to 50% of nail disorders. Although several surveys have been conducted in different parts of the world, there have been no multicenter epidemiologic surveys of onychomycosis in North America. OBJECTIVE: A 12-center study was undertaken to (1) determine the frequency of onychomycosis, (2) identify organisms recovered from the nails, and (3) determine the antifungal susceptibility of isolates. METHODS: A total of 1832 subjects participated in this study and completed a comprehensive questionnaire, and nail clippings were collected for potassium hydroxide examination and culturing. RESULTS: The frequency of onychomycosis, as defined by the presence of septate hyphae on direct microscopy and/or the recovery of a dermatophyte, was found to be 13.8%. In general, the dermatophyte isolates were susceptible to the antifungals tested. CONCLUSION: Because of the limited number of large-scale studies, the baseline incidence is not firmly established. However, the higher frequency of onychomycosis in this study may confirm the suspected increase in incidence of disease in North America.

Adolescent↗
PubMed2000

Novel TSHR germline mutation (Met463Val) masquerading as Graves' disease in a large Welsh kindred with hyperthyroidism.

Hereditary nonautoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin (TSH) receptor (TSHR) gene. We describe an extended Welsh kindred with toxic thyroid hyperplasia affecting 8 family members in three generations and a history consistent with thyrotoxicosis in a further three generations now deceased. A novel heterozygous germline mutation (ATG --> GTG; Met463Val) was identified in the second membrane spanning TSHR region in 6 relatives with thyrotoxicosis and goiter and absence of TSHR antibodies. Screening of 5 additional family members led to the identification of 2 siblings with the mutation, who were asymptomatic at the time, although subsequent thyroid function tests in these children showed suppressed serum TSH and increased serum free triiodothyronine (FT3) and free thyroxine (FT4) concentrations. Functional studies of the novel TSHR germline mutation demonstrated a constitutive activation of the cAMP pathway, which in the thyroid controls both thyroid hormone production and stimulation of thyroid growth. The molecular diagnosis in this family has clinical implications: genetic counseling is required, and primary thyroid ablation should be advocated as the preferred treatment in the patients with the constitutively activating TSHR germline mutation.

Animals↗
PubMed2000

Antifungal susceptibility testing of dermatophytes: establishing a medium for inducing conidial growth and evaluation of susceptibility of clinical isolates.

A standardized reference method for dermatophyte in vitro susceptibility testing is lacking. In a previous study, Norris et al. (H. A. Norris, B. E. Elewski, and M. A. Ghannoum, J. Am. Acad. Dermatol. 40(6, part 2):S9-S13) established the optimal medium and other growth variables. However, the earlier study did not address two issues: (i) selection of an optimal medium for conidial formation by dermatophytes and (ii) validation of the method with a large number of dermatophytes. The present study addresses these two points. To select which agar medium best supported conidial growth, representative isolates of dermatophytes were grown on different agars. Preliminary experiments showed that only oatmeal cereal agar supported the production of conidia by Trichophyton rubrum. We tested the abilities of 251 T. rubrum isolates to form conidia using three different cereal agars and potato dextrose agar. Overall, oatmeal cereal and rice agar media were comparable in their abilities to support T. rubrum conidial growth. Next, we used the oatmeal cereal agar for conidial formation along with the optimal conditions for dermatophyte susceptibility testing proposed by Norris et al. and determined the antifungal susceptibilities of 217 dermatophytes to fluconazole, griseofulvin, itraconazole, and terbinafine. Relative to the other agents tested, terbinafine possessed the highest antifungal activity against all of the dermatophytes. The mean +/- standard error of the mean MICs of fluconazole, itraconazole, terbinafine, and griseofulvin were 2.07 +/- 0.29, 0.13 +/- 0.01, 0.002 +/- 0.0003, and 0.71 +/- 0.05 microgram/ml, respectively. This study is the first step in the identification of optimal conditions that could be used for the standardization of the antifungal susceptibility testing method for dermatophytes. Inter- and intralaboratory agreement as well as clinical correlations need to be established.

Antifungal Agents↗
PubMed1999

Ontario, Canada, high school teachers as enforcers in the war on drugs: what their students see and say.

This paper examines how high school teachers interact with students on the subject of marijuana. Results, based on 49 focus groups with 278 high school students in Ontario, Canada, reveal three basic assumptions of the students: 1) only some teachers can actually tell when a student is high on marijuana; 2) many teachers have tried marijuana or continue to use it; and 3) individual teachers vary in how they respond to students who are high. Results suggest that changes in the relationship between marijuana and authority account in large part for the seeming reluctance of so many teachers to exercise their mandate to discipline students who use marijuana. The reasons for this are twofold: 1) many teachers do not see use of marijuana of and by itself as a threat to their authority; and 2) teachers who choose to confront users run the risk of having their authority and independence of action undermined once they report infractions to administrators who have authority over teachers and students alike.

Adolescent↗
PubMed1999

The Scottish breast screening programme's experience of monitoring interval cancers.

OBJECTIVES: To present the Scottish interval cancer data from 1991 to 1995, compare the Scottish experience with results published by other programmes and trials, and document appropriate methodologies to achieve maximum ascertainment of interval cancers. SETTING: Scottish breast screening programme (part of the UK National Health Service breast screening programme). METHODS: Interval cancers were identified by linking breast screening data with registrations of invasive breast cancers from the National Scottish Cancer Register. The main outcome measures were the numbers, rates, and proportionate incidence of interval cancers, and rates of total and small (< 10 mm) screen detected invasive cancers diagnosed in this cohort of women. SUBJECTS: Women who attended the Scottish breast screening programme (Scottish NHSBSP) from 1 April 1991 to 31 March 1995. RESULTS: Interval cancer rates of 4.8, 12.1, and 12.1 per 10,000 women screened were calculated for the first, second, and third year after the last negative screen. Expressed as a proportion of the underlying incidence, the figures are 23%, 60%, and 59%. CONCLUSIONS: The Scottish data are comparable with those reported by other UK NHS breast screening programmes for the first and second years after the last negative screen. The interval cancer rate for the third year is appreciably lower. A longer follow up period would be of interest to provide greater evidence on which to base comparisons. Ascertainment of interval cancers depends vitally on the availability of complete, accurate, and timely national cancer registration data and highlights the value of national datasets.

Breast Neoplasms↗
PubMed1999

Zolmitriptan is effective for the treatment of persistent and recurrent migraine headache.

Zolmitriptan is a 5-HT1B/1D receptor agonist for the acute treatment of migraine. This study examined the efficacy of a second dose of zolmitriptan for the treatment of persistent or recurrent headache. Part 1 was a randomised, placebo-controlled, double-blind evaluation of 2.5 mg and 5 mg zolmitriptan for the treatment of persistent migraine headache, two hours after an initial dose of 2.5 mg zolmitriptan. In part 2 (open-label), patients treated the first two attacks with 2.5 mg zolmitriptan, thereafter patients could treat any initial, persistent or recurrent migraine headache with 2.5 mg or 5 mg zolmitriptan. The unique design of this trial allowed patients to adjust their treatment to attain maximum headache relief and control of their disease. Of 2800 patients treating an initial migraine headache in Part 1, 989 patients took a second dose to treat persistent headache of moderate or severe intensity. Headache response rates were similar across the three treatment groups, but the pain-free response rate was significantly higher with 5 mg zolmitriptan than with placebo (p < 0.001). In Part 2, 2499 patients treated 49,784 migraine attacks (excluding the first two attacks, which had to be treated with 2.5 mg zolmitriptan), of which 66% required only a single dose of zolmitriptan. Patients treated 22% of attacks with a second dose of zolmitriptan for persistent headache. A headache response was achieved in 80% and 73% of persistent headaches treated with 2.5 mg or 5 mg zolmitriptan, respectively. Corresponding pain-free responses following treatment of persistent headaches of any intensity were 64% and 52%. Eight per cent of attacks were treated with a second dose of zolmitriptan for moderate or severe recurrent headache. A headache response was achieved in 90% and 86% of moderate/severe attacks, with a pain-free response in 78% and 70% of attacks of any intensity treated with 2.5 mg and 5 mg, respectively. Zolmitriptan was well tolerated. In conclusion, 2.5 mg and 5 mg zolmitriptan are highly effective in treating both persistent and recurrent migraine headache.

Adolescent↗
PubMed1998

Analysis of the genomic organisation of a small chromosome of Leishmania braziliensis M2903 reveals two genes encoding GTP-binding proteins, one of which belongs to a new G-protein family and is an antigen.

Leishmania braziliensis M2903 contains a highly amplified small chromosome. This work is aimed at resolving its structural organization and determining whether this unusual chromosome contains specific genes encoding proteins with important functions in disease pathology or drug resistance. Our results show that the M2903 250-kb small chromosome contains LD1 sequences and has an inverted repeat structure. The LD1 sequences and two cDNAs (cDNA2 and cDNA53) were mapped on a cosmid contig, and the two cDNAs and the corresponding genomic fragments from the small chromosome were sequenced. The gene encoding cDNA2 predicts a putative GTP-binding protein with homology to other GTP-binding proteins only in the G-1 domain region; however, four other conserved motifs can be recognized. Sequence similarity to cDNA53 is located in at least five chromosomes, and its small chromosome copy is a pseudogene. An open reading frame downstream of the cDNA53 pseudogene predicts another GTP-binding protein that belongs to a new G-protein family with an unusual conserved GTP-binding domain and a newly characterized conserved sequence motif. A portion of this GTP-binding protein gene was studied previously in L. aethiopica as a recombinant antigen that reacts with human antibodies.

Amino Acid Sequence↗
PubMed1998

Slow cooperative folding of a small globular protein HPr.

The folding of an 85-residue protein, the histidine-containing phosphocarrier protein HPr, has been studied using a variety of techniques including DSC, CD, ANS fluorescence, and NMR spectroscopy. In both kinetic and equilibrium experiments the unfolding of HPr can be adequately described as a two-state process which does not involve the accumulation of intermediates. Thermodynamic characterization of the native and the transition states has been achieved from both equilibrium and kinetic experiments. The heat capacity change from the denatured state to the transition state (3. 2 kJ mol-1 K-1) is half of the heat capacity difference between the native and denatured states (6.3 kJ mol-1 K-1), while the solvent accessibility of the transition state (0.36) indicates that its compactness is closer to that of the native than that of the denatured state. The high value for the change in heat capacity upon unfolding results in the observation of cold denaturation at moderate denaturant concentrations. Refolding from high denaturant concentrations is, however, slow. The rate constant of folding in water, (14.9 s-1), is small compared to that reported for other proteins of similar size under similar conditions. This indicates that very fast refolding is not a universal character of small globular proteins which fold in the absence of detectable intermediates.

Bacterial Proteins↗
PubMed1998

Historical perspectives on the shifting boundaries around youth and alcohol. The example of pre-industrial England, 1350-1750.

This study identifies some of the factors that account for why young males are permitted to drink in some cultures and not in others. The primary materials consulted in this study suggest that in the case of pre-industrial England the same norms governed both adult and juvenile access to alcohol in the late medieval period, and that separate standards for adults and juveniles only emerged some time after 1500. The materials also suggest that the norms governing juvenile access to alcohol were at their most restrictive when adult and juvenile labour were both in low demand, and when childhood was a state from which an individual exited at an early age, but adulthood was a status that was postponed for a large proportion of the population. Apparent changes in the norms governing juvenile access to alcohol also coincided with two other developments in the early modern period. These were: (1) the gradual transformation of drinking into an essentially recreational activity conducted outside the home and among groups consisting largely or entirely of males; and (2) the introduction of new and potentially more intoxicating alcoholic beverages, first in the form of beer, and later in the form of cheap spirits distilled from grain.

Adolescent↗
PubMed1998

A multidisciplinary approach to hospital-based drug cost containment.

OBJECTIVE: To develop and implement a range of strategies to control rising drug expenditure in a teaching hospital. METHOD: A multidisciplinary team was established to survey drug use and to identify areas where drug wastage was occurring. Once target areas were identified, strategies were developed and implemented and drug expenditure monitored prospectively. RESULTS: Communication and education about optimum drug use, efficient drug handling and therapeutic drug substitution were identified as areas for action. Antibiotic prescribing, outpatient prescribing and expenditure on new drugs were identified as target areas for cost savings. Compared to previous years, the rate of increase in drug expenditure on antibiotics was reduced by over 5000 pound sterling, from a baseline of 552 278 pound sterling over the study period compared to an increase of 65 984 pound sterling for the previous corresponding period. CONCLUSION: We believe that despite the short-coming of the study, which adopted an open design without a control group, it demonstrates that effective cost-containment strategies can be implemented by multidisciplinary teams if they are given sufficient support by senior management.

Cost Control↗