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Biomedical subjects

A R Clark

Publications and source records attributed to A R Clark.

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

Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability.

Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-alpha) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-alpha mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-alpha 3' untranslated region. The p38 pathway is required for the induction of TNF-alpha RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-alpha gene expression at a posttranscriptional level.

3' Untranslated Regions↗
PubMed2000

Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade.

The translation of tumour necrosis factor alpha (TNFalpha) mRNA is regulated by the stress-activated protein kinase p38, which also controls the stability of several pro-inflammatory mRNAs. The regulation of TNFalpha gene expression in a mouse macrophage cell line RAW264.7 was re-examined using an inhibitor of stress-activated protein kinases. Stimulation of these cells with bacterial lipopolysaccharide resulted in stabilisation of TNFalpha mRNA, which was reversed by specific inhibition of p38. An adenosine/uridine-rich element from the TNFalpha 3' untranslated region conferred p38-sensitive decay in a tetracycline-regulated mRNA stability assay. Therefore the p38 pathway also controls TNFalpha mRNA turnover.

3' Untranslated Regions↗
PubMed2000

Measurement of the W-->taunu production cross section in pp collisions at square root s=1.8 TeV.

We report on a measurement of sigma(pp-->W+X)B(W-->taunu) in pp collisions at sqrt[s]=1.8 TeV at the Fermilab Tevatron. The measurement is based on an integrated luminosity (lum) of 18 pb-1 of data collected with the D0 detector during 1994-1995. We find that sigma(pp-->W+X)B(W-->taunu)=2.22+/-0.09 (stat)+/-0. 10 (syst)+/-0.10 (lum) nb. Lepton universality predicts that the ratio of the tau and electron electroweak charged current couplings to the W boson, gWtau/gWe, be unity. We find gWtau/gWe=0.980+/-0.031, in agreement with lepton universality.

Journal Article↗
PubMed2000

Probing Balitsky-Fadin-Kuraev-Lipatov dynamics in the dijet cross section at large rapidity intervals in pp collisions at sqrt[s]=1800 and 630 GeV.

Inclusive dijet production at large pseudorapidity intervals (Deltaeta) between the two jets has been suggested as a regime for observing Balitsky-Fadin-Kuraev-Lipatov (BFKL) dynamics. We have measured the dijet cross section for large Deltaeta in pp collisions at sqrt[s]=1800 and 630 GeV using the D0 detector. The partonic cross section increases strongly with the size of Deltaeta. The observed growth is even stronger than expected on the basis of BFKL resummation in the leading logarithmic approximation. The growth of the partonic cross section can be accommodated with an effective BFKL intercept of alphaBFKL(20 GeV)=1.65+/-0.07.

Journal Article↗
PubMed2000

Treatment of psoriasis: an algorithm-based approach for primary care physicians.

Psoriasis is characterized by red, thickened plaques with a silvery scale. The lesions vary in size and degree of inflammation. Psoriasis is categorized as localized or generalized, based on the severity of the disease and its overall impact on the patient's quality of life and well-being. Patient education about the disease and the treatment options is important. Medical treatment for localized psoriasis begins with a combination of topical corticosteroids and coal tar or calcipotriene. For lesions that are difficult to control with initial therapy, anthralin or tazarotene may be tried. The primary goal of therapy is to maintain control of the lesions. Cure is seldom achieved. If control becomes difficult or if psoriasis is generalized, the patient may benefit from phototherapy, systemic therapy and referral to a physician who specializes in the treatment of psoriasis.

Adrenal Cortex Hormones↗
PubMed2000

The emerging role of physician assistants in the delivery of dermatologic health care.

The NAMCS provides a wealth of information on use of PAs in all practices, including dermatology. Two important points regarding the NAMCS and SDPA data are addressed here: the number of visits to PAs for dermatologic symptoms and the expected growth of PA use in dermatologists' offices. Dermatologic symptoms were evaluated frequently by PAs, accounting for 14% of PA visits. These statistics do not address the number of referrals those PAs made to dermatologists. Perhaps PAs as a group should be targeted for increased dermatologic education, particularly stressing the need for appropriate referral to a dermatologist. PAs could increase the number of dermatology referrals from primary care offices with improved understanding of the importance of the dermatologist in the management of patients' overall skin health. At projected growth rates, the number of PAs employed by dermatologists should exceed 500 by the end of 2000. Most of this growth has been in private practices and rarely in HMOs or in large multispecialty clinics. There are a number of reasons for this growth, as follows: A PA may help reduce the patient load on the dermatologist, especially with sameday appointments and drop-ins. Some dermatologists are moving away from clinical dermatology into cosmetics, which not only leaves a vacuum in clinical dermatology, but also creates job opportunities for PAs in cosmetic dermatology. Regarding managed care growth, PAs can have a positive impact on the problem of having to see more patients for less money. PAs are cost-effective. In the 1998 SDPA survey, the ratio of billings generated (production) to gross income for the average dermatology PA ranged from 3:1 to 6:1. Even with inexperienced PAs new to dermatology, this ratio was usually at least 2:1 at the end of the first year. PAs can cover satellite offices, allowing for practice expansion. Effective with the new Medicare laws of January 1, 1998, PAs can now see new Medicare patients or Medicare patients with new conditions without the physician being on site, opening up the possibility for satellite offices in remote areas. Just as dermatologists may move toward specialization in surgery, cosmetics, or medical dermatology, PAs may do the same, filling a niche in a particular practice. As in other specialties, patient acceptance of seeing dermatology PAs has not been a significant problem. Continued access to the dermatologist remains unfettered, but, over time, many patients become willing to see either. Are PAs likely to become future competitors of dermatologists? Genuinely concerned dermatologists worry that a dermatology-trained PA will become part of a gatekeeper system that impedes patient access to dermatologists. This is not happening and is not at all likely to become a trend, for a number of reasons. First, primary care cannot compete with dermatology practices in remuneration for PAs. Just as financial benefits in high-production specialty practices entice physicians, the same benefits entice PAs as well. Second, according to member surveys of the SDPA, virtually 100% of fellow members work with dermatologists. Although PAs can work in any type of practice and evaluate dermatologic symptoms just as a general practitioner would, PAs who specialize in dermatology primarily practice with dermatologists, a collegial association most PAs seek out. PAs have steadfastly maintained their dependent, noncompetitive relationship with physicians and would not have it any other way. Although PAs see a good number of patients (2.8 million) with dermatologic symptoms, the NAMCS data indicate that most (72%) of these patients are also seen by a physician. Third, physicians are ultimately responsible for the actions of their PA employee. A general practitioner not trained to perform excisions or manage certain dermatologic conditions should not allow a PA to perform such duties. Similar to much of medicine, the PA profession continues to evolve, with many members moving awa

Delivery of Health Care↗
PubMed2000

Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade.

A tetracycline-regulated reporter system was used to investigate the regulation of cyclooxygenase 2 (Cox-2) mRNA stability by the mitogen-activated protein kinase (MAPK) p38 signaling cascade. The stable beta-globin mRNA was rendered unstable by insertion of the 2, 500-nucleotide Cox-2 3' untranslated region (3' UTR). The chimeric transcript was stabilized by a constitutively active form of MAPK kinase 6, an activator of p38. This stabilization was blocked by SB203580, an inhibitor of p38, and by two different dominant negative forms of MAPK-activated protein kinase 2 (MAPKAPK-2), a kinase lying downstream of p38. Constitutively active MAPKAPK-2 was also able to stabilize chimeric beta-globin-Cox-2 transcripts. The MAPKAPK-2 substrate hsp27 may be involved in stabilization, as beta-globin-Cox-2 transcripts were partially stabilized by phosphomimetic mutant forms of hsp27. A short (123-nucleotide) fragment of the Cox-2 3' UTR was necessary and sufficient for the regulation of mRNA stability by the p38 cascade and interacted with a HeLa protein immunologically related to AU-rich element/poly(U) binding factor 1.

Anti-Bacterial Agents↗
PubMed2000

Transmittance properties of flurandrenolide tape for psoriasis: helpful adjunct to phototherapy.

BACKGROUND: Flurandrenolide tape is a valuable agent in the treatment of lichen simplex chronicus and in psoriasis. The corticosteroid is helpful for reducing the symptoms and induration of the lichen simplex chronicus lesion, and occlusion of the lesion with the tape reduces the patient's opportunity to rub and scratch the affected area. OBJECTIVES: The purpose of this study was to determine to what extent flurandrenolide tape may block ultraviolet (UV) light and interfere with phototherapy of psoriasis. METHODS: Flurandrenolide tape was applied to quartz spectroscopy cuvettes, and the absorption spectrum was determined using a Beckman DU-600 spectrophotometer. The effect of the tape on UV light transmission was also determined using our UVA-UVB office phototherapy unit. RESULTS: Flurandrenolide tape has considerable UV absorption in the UVC range with less absorption in the UVB and UVA range. The transmittance is greater (less absorption) with longer wavelengths. There was greater UV absorption in the UVB range than in the UVA range. CONCLUSION: Although flurandrenolide tape may be left in place during PUVA therapy, adjustment of UV dose or removal of the tape is probably needed during UVB phototherapy.

Administration, Topical↗
PubMed1999

p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes.

p38 mitogen-activated protein kinase (MAPK) is activated by inflammatory stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor. We have previously shown that the pyridinyl imidazole SB 203580, which inhibits it, blocks the interleukin-1 induction of cyclooxygenase-2 (COX-2) and matrix metalloproteinase 1 and 3 mRNAs in fibroblasts. Here we explore the role of p38 MAPK in the response of human monocytes to LPS. 0.1 microM SB 203580 significantly inhibited the LPS induction of COX-2 and tumor necrosis factor protein and mRNAs. The activity of MAPK-activated protein kinase-2 (a substrate of p38 MAPK) in the cells was commensurately reduced. Some isoforms of c-jun N-terminal kinase (which is also activated by LPS) are sensitive to SB 203580; the inhibitor had little effect on monocyte c-jun N-terminal kinases up to 2 microM. We investigated the mechanism of inhibition of COX-2 induction. Transcription (measured by a nuclear run-on assay) was 60% inhibited by SB 203580 (2 microM). Importantly, we found that p38 MAPK was essential for stabilizing COX-2 mRNA: when cells stimulated for 4 h with LPS were treated with actinomycin D, COX-2 mRNA decayed slowly. Treatment of stimulated cells with 2 microM SB 203580 caused a rapid disappearance of COX-2 mRNA, even with actinomycin D present. We conclude p38 MAPK plays a role in the transcription and stabilization of COX-2 mRNA.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1998

A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA.

The mechanism by which p38 mitogen-activated protein kinase (MAPK) regulates the induction of cyclooxygenase (COX)-2 by interleukin-1 (IL-1) has been investigated in HeLa cells. SB 203580, an inhibitor of p38 MAPK, in the range 0.1-1 microM inhibited IL-1-stimulated PGE2 (but not arachidonic acid) release and this was associated with inhibition of induction of COX-2 protein and mRNA. IL-1 stimulated COX-2 transcription in HeLa cells about 2-fold as judged by both reporter gene and nuclear run-on assays. The inhibitor had no significant effect on this. However, in cells previously stimulated with IL-1 it caused rapid destabilisation of COX-2 mRNA independently of on-going transcription. The results suggest a novel function for p38 MAPK in the regulation of mRNA stability.

Arachidonic Acids↗
PubMed1998

Psoriasis.

Psoriasis is a common skin condition that can be controlled in nearly every patient. The diagnosis of psoriasis is generally made on the basis of identification of skin lesions of characteristic morphology in characteristic locations. A variety of treatments and resources are available to patients with psoriasis and to the physicians who treat them. Development of an appropriate treatment regimen is facilitated by categorization of psoriasis into localized versus generalized forms.

Diagnosis, Differential↗
PubMed1998

Papular dermatitis (subacute prurigo, "itchy red bump" disease): pilot study of phototherapy.

BACKGROUND: Some patients with a subacute or chronic pruritic erythematous papular eruption are refractory to treatment. We previously described a number of these patients with papular dermatitis or subacute prurigo. OBJECTIVE: The purpose of this study was to examine the effectiveness of different types of phototherapy for treatment of papular dermatitis. METHODS: We reviewed the medical records of 11 patients who were diagnosed with papular dermatitis and who underwent phototherapy within the last 5 years. RESULTS: Eleven patients had a total of 17 phototherapy courses: psoralen-UVA (PUVA; 9), UVA/UVB light (3), and UVB alone (5). Within the PUVA treatment group, three of nine patients experienced total clearing, and six of nine patients experienced partial improvement. Although patients in all groups relapsed with time, overall the PUVA-treated patients had the best response rate and the best chance of the condition remaining clear after treatment was stopped. CONCLUSION: PUVA may be an effective treatment for papular dermatitis. The frequency of relapse indicates that maintenance treatments may be necessary for long-term control of the disease.

Aged↗
PubMed1998

Disappointing initial results with transurethral alprostadil for erectile dysfunction in a urology practice setting.

PURPOSE: We evaluate the response to intraurethral alprostadil administration using the Medicated Urethral System for Erection (MUSE) in unselect men with a history of erectile dysfunction. We determine the effects on blood pressure during in office monitoring and assess safety of this form of treatment. We compare the efficacy of MUSE in an office setting with the placebo controlled pivotal study. MATERIALS AND METHODS: A total of 115 men with erectile dysfunction underwent in office testing with MUSE following the algorithm recommended by the manufacturer and outlined in the original pivotal study. Patients were asked to rate the rigidity of erection from 1 to 5 with scores 4 and 5 for erections sufficient for intercourse, and level of discomfort from 1 (very uncomfortable) to 5 (very comfortable) at 15-minute intervals. Patients who did not achieve a sufficient erection were scheduled to return for in office testing using the next higher dose up to 1,000 microg. Patient supine and sitting blood pressures were recorded by a nurse before and every 15 minutes after administration. Telephone contact with patients 2 to 3 months after the last in office testing was made to determine whether they were using the system. RESULTS: Mean plus or minus standard deviation rigidity scores independent of dosage increased from 2.34+/-0.99 at 15 minutes to 2.49+/-0.96 at 30 minutes and decreased thereafter. Although the 1,000 microg. dosage resulted in highest mean score at all times, the differences between dosages were not significant. Rigidity score 4 or 5 was achieved in 13.2% (500 microg.) and 30% (1,000 microg.) of patients at 30 minutes. Mean level of discomfort was 3.6+/-1.2 at 15 minutes and improved thereafter. Comfort levels were not significantly different among dosages. Overall, at 15 minutes 16.8% of patients were uncomfortable (score 1 or 2) and 41.3% were somewhat uncomfortable (1, 2 or 3). For all dosages supine and sitting systolic and diastolic blood pressures decreased significantly from before treatment to 15 minutes and stayed lower during monitoring. Defined by strict criteria 41.2% of patients experienced orthostatic hypotension during in office testing. A total of 21 patients had adverse events, including pain, discomfort and burning in the penis (the most common), dizziness and chest pain. One patient had a syncopal episode and fell in the office. At last followup only 18.6% of the tested patients continued to use MUSE at home, while the remainder discontinued treatment due to pain, insufficient erections for intercourse and cost. CONCLUSIONS: We were unable to achieve similar results to the pivotal study following manufacturer instructions and the algorithm provided by that study. Independent of age and etiology no more than 30% of patients at any given time using any dose achieved erections sufficient for intercourse during in office testing. Because of this limited efficacy, discomfort, pain and burning associated with treatment, and cost, more than 80% of patients did not continue to use MUSE at home.

Adult↗
PubMed1998

Inspiratory flow rate and dynamic lung function in cystic fibrosis and chronic obstructive lung diseases.

STUDY OBJECTIVES: The peak inspiratory flow rates (PIFRs) generated by cystic fibrosis (CF) and COPD patients through a range of clinically relevant resistances have not yet been reported (to our knowledge). The objectives of this study were to (1) explore a relevant range of resistive loads and address whether patients with stable CF and COPD can generate the PIFR sufficient to disperse dry-powder inhalants (DPI) and (2) determine whether the optimal inspiratory flow rate effective for delivery of aerosolized pharmacologic therapeutic agents can be attained with a comfort rating acceptable to subjects. DESIGN: Prospective, controlled, subject-blinded study. SETTING: Pulmonary function laboratory at the VA Palo Alto Health Care System. PATIENTS OR PARTICIPANTS: Thirty-six subjects, including 12 healthy volunteers, 12 subjects with CF, and 12 subjects with COPD were studied. MEASUREMENTS: Studies of dynamic lung function and PIFR without and with varying resistances were obtained at a single laboratory visit. RESULTS: Dynamic lung function and PIFR varied inversely with the resistive load for all patient groups and did not correlate with the disease severity, as indicated by FEV1 of percent predicted. The average subjective comfort rating for any given resistive load was similar for subjects with CF and COPD. CONCLUSIONS: These results support the conclusion that subjects with stable CF and COPD of varying severity can comfortably generate the necessary flow rates to operate new and currently available DPIs over a wide range of inspiratory resistances.

Adolescent↗
PubMed1998

The incidence of allergic contact dermatitis in patients with psoriasis vulgaris.

BACKGROUND: Contact dermatitis is said to be rare in psoriasis patients, possibly because of accelerated epidermal turnover, the isomorphic (Koebner) response, and lymphocyte functional alterations. OBJECTIVE: To identify contact allergy in patients with psoriasis. METHODS: A written questionnaire was completed by 100 patients with psoriasis about contact history, flare factors for psoriasis, topical skin care, medications, and occupational/hobby exposures. Of these patients, 20 agreed to be patch tested with a standard screening series (Hermal) and a 20-item psoriasis patch-test series that included ingredients that might be found in topical psoriasis products. RESULTS: Of the 100 patients, eight suspected a topical medication caused a reaction that worsened their psoriasis, 29 gave a history of atopy, 11 reported reactions to metal jewelry, and 29 reported an allergy to poison ivy. Patch-test results identified four of the 20 patients with six positive patch tests to the materials tested: three of the six positive tests were interpreted as relevant to the patient's psoriasis (coal tar, ethylenediamine and dithranol), two patients tested positive to nickel and one to thimerosal. Five patients had irritant reactions to dithranol. CONCLUSIONS: In this small study, 20% of self-selected psoriasis patients had positive allergic reactions on patch testing. A screening contact and atopic history in psoriasis patients may help to identify a subset of patients who could benefit from a search for more relevant contact allergens with patch test evaluation. This could improve treatment strategies and possibly reduce disability.

Dermatitis, Allergic Contact↗