Biomedical subjects

Daniel Stewart

Publications and source records attributed to Daniel Stewart.

13 recordsLinked to original sources

PubMed2006

Diffusion tensor imaging in schizophrenia.

BACKGROUND: Alignment of white matter axons as inferred from diffusion tensor imaging has indicated changes in schizophrenia in frontal and frontotemporal white matter. METHODS: Diffusion tensor anisotropy and anatomical magnetic resonance images were acquired in 64 patients with schizophrenia and 55 normal volunteers. Anatomical images were acquired with a magnetization prepared rapid gradient echo sequence, and diffusion tensor images used a pulsed gradient spin-echo acquisition. Images were aligned and warped to a standard brain, and anisotropy in normal volunteers and patients was compared using significance probability mapping. RESULTS: Patients showed widespread areas of reduced anisotropy, including the frontal white matter, the corpus callosum, and the frontal longitudinal fasciculus. CONCLUSIONS: These findings, which are consistent with earlier reports of frontal decreases in anisotropy, demonstrate that the effects are most prominent in frontal and callosal areas and are particularly widespread in frontal white matter regions.

Adolescent↗

PubMed2005

A randomized study of the safety, absorption and efficacy of pimecrolimus cream 1% applied twice or four times daily in patients with atopic dermatitis.

BACKGROUND: Pimecrolimus cream 1% (Elidel), a non-steroid inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis, without corticosteroid-related side effects such as skin atrophy. It is indicated for twice-daily application. More frequent applications might be expected either to enhance efficacy or increase toxicity. This study compared the safety, efficacy and systemic absorption of pimecrolimus administered twice daily (recommended dose) and four times daily early in the treatment of patients with moderate to severe atopic dermatitis. METHODS: Adolescent and adult patients with moderate to severe atopic dermatitis were randomly assigned to a twice daily (BID) treatment group (n = 24) or a four times daily (QID) group (n = 25). During days 1-7, patients in the QID group applied pimecrolimus four times daily, and patients in the BID group applied pimecrolimus twice daily plus vehicle equivalent twice daily. During days 8-21, all patients were required to use pimecrolimus twice daily and had the option to use up to two further daily treatments (pimecrolimus in the QID group and vehicle equivalent in the BID group). Blood sampling occurred 2, 4, and 6 hours after the first morning application on days 1 and 5 and then prior to the first morning application on days 8 and 15, and any time on day 22. RESULTS: Only 3 (12%) QID patients and 4 (17%) BID patients reported adverse events (primarily mild, transient application-site burning) with no significant difference between treatment groups in the frequency, type, or severity of adverse events. The median daily number of applications in the QID group during days 8-21 when two additional doses were optional remained at four. Pimecrolimus blood levels from a subgroup of 22 patients showed no difference in systemic exposure between the two dosing regimens. All but three (one in the QID group, two in the BID group) patients had blood levels below the limit of quantification; the highest single blood level of pimecrolimus measured in any patient was 1.37 ng/ml (QID group). Both the QID and BID regimens improved the signs and symptoms of atopic dermatitis similarly as measured by improvements in pruritus severity score, Investigator's Global Assessment, Eczema Area and Severity Index, percentage of body surface area affected, and patient's self-assessment of disease control. CONCLUSIONS: The data suggest that increasing pimecrolimus application from twice daily to four times daily to treat moderate to severe atopic dermatitis for up to 3 weeks does not alter the safety profile nor does it increase the efficacy of treatment. Systemic absorption of pimecrolimus applied BID and QID is minimal and is not different between dosing regimens. Patients and physicians familiar with the potential hazards of overuse of topical corticosteroids should be reassured that if pimecrolimus is applied at twice the recommended BID dose for short periods of time, there is no effect on safety, tolerability, or systemic absorption.

Administration, Topical↗

PubMed2005

Randomized, double-blind, placebo-controlled study evaluating the lidocaine/tetracaine patch for induction of local anesthesia prior to minor dermatologic procedures in geriatric patients.

BACKGROUND: Topical anesthetics offer a noninvasive method of anesthesia. OBJECTIVE: To evaluate the efficacy and safety of the lidocaine/tetracaine patch, a 1:1 (wt:wt) eutectic mixture of lidocaine and tetracaine, for local anesthesia before minor dermatologic procedures in geriatric patients. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study, 79 patients over the age of 65 years received a 30-minute application of either the lidocaine/tetracaine patch or placebo immediately before a shave biopsy or superficial excision. The primary measure of efficacy was patient assessment of procedural pain using the visual analog scale (VAS). Secondary efficacy end points included patient, investigator, and independent observer assessments. RESULTS: There was a statistically significant difference (p = .041) in patient ratings of pain by VAS score in the active group (9.5 mm) compared with the placebo group (22.5 mm). None of the secondary end points showed a statistically significant difference between groups. No adverse events were reported. CONCLUSION: The lidocaine/tetracaine patch is a safe and effective method for noninvasive induction of local anesthesia for minor dermatologic procedures in patients over the age of 65 years.

Aged↗

PubMed2005

Combination sodium sulfacetamide 10% and sulfur 5% cream with sunscreens versus metronidazole 0.75% cream for rosacea.

Topical metronidazole and combination sodium sulfacetamide and sulfur commonly are used to treat rosacea. Recently, the relative efficacy and safety of sodium sulfacetamide 10% and sulfur 5% cream with sunscreens (Rosac Cream) (n = 75) and metronidazole 0.75% cream (Metrocream) (n = 77) were compared in an investigator-blinded, randomized, parallel-group study at 6 sites. After 12 weeks of treatment with sodium sulfacetamide 10% and sulfur 5% cream with sunscreens, there was a significantly greater percentage reduction (80%) in inflammatory lesions compared with metronidazole 0.75% cream (72%)(P = .04), as well as a significantly greater percentage of subjects with improved erythema (69% vs 45%, respectively; P = .0007). In addition, the sodium sulfacetamide 10% and sulfur 5% cream with sunscreens group had a significantly greater proportion of subjects with success in global improvement at week 12 compared with the metronidazole 0.75% cream group (79% vs 59%, respectively; P = .01). There was no significant difference between treatment groups in the percentage of subjects with improvement in investigator global severity. Overall tolerance was good or excellent in 85% of subjects in the sodium sulfacetamide 10% and sulfur 5% cream with sunscreens group and in 97% of subjects in the metronidazole 0.75% cream group. Seven subjects had poor tolerance to the sodium sulfacetamide 10% and sulfur 5% cream with sunscreens, possibly caused by a sulfa drug allergy.

Analysis of Variance↗

PubMed2004

A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris.

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.

Acne Vulgaris↗

PubMed2003

Ciclopirox gel in the treatment of patients with interdigital tinea pedis.

UNLABELLED: BACKGROUND Tinea pedis (athlete's foot) is the most common fungal infection in the general population. Ciclopirox, a broad-spectrum hydroxypyridone antifungal, has proven efficacy against the organisms commonly implicated in tinea pedis; Trichophyton rubrum, T.mentagrophytes and Epidermophyton floccosum. OBJECTIVE: Two multicenter, double-blind, clinical studies compared the efficacy and safety of ciclopirox gel with that of its vehicle base in subjects with moderate interdigital tinea pedis with or without plantar involvement. METHODS: Three hundred and seventy-four subjects were enrolled and randomized to one of two treatment groups: ciclopirox gel 0.77%, or ciclopirox gel vehicle, applied twice daily for 28 days, with a final visit up to day 50. The primary efficacy variable was Treatment Success defined as combined mycological cure and clinical improvement >/= 75%. Secondary measures of effectiveness were Global Clinical Response, Sign and Symptom Severity Scores, Mycological Evaluation (KOH examination and final culture result), Mycological Cure (negative KOH and negative final culture results) and Treatment Cure (combined clinical and mycological cure). RESULTS: At endpoint (final post-baseline visit), 60% of the ciclopirox subjects achieved treatment success compared to 6% of the vehicle subjects. At the same time point, 66% of ciclopirox subjects compared with 19% of vehicle subjects were either cleared or had excellent improvement. Pooled data showed that 85% of ciclopirox subjects were mycologically cured, compared to only 16% of vehicle subjects at day 43, 2 weeks post-treatment. CONCLUSIONS: Ciclopirox gel 0.77% applied twice daily for 4 weeks is an effective treatment of moderate interdigital tinea pedis due to T. rubrum, T. mentagrophytes and E. floccosum and is associated with a low incidence of minor adverse effects.

Administration, Topical↗

PubMed2003

Nasal reconstruction.

Nasal defects commonly seen by plastic surgeons result from trauma, burn injury, or tumor resection. While nasal reconstruction is one of the oldest plastic surgery endeavors, techniques continue to evolve and be modified. Grafts and local flaps are used in smaller defects. Larger and complex defects are best reconstructed following the aesthetic unit principle. These defects also require replacement of all lost tissues to provide nasal lining, skeletal support, and skin coverage. Careful analysis of the defect and reliance on these general guidelines will allow for less obvious nasal reconstruction and a more natural appearance and function.

Esthetics↗

PubMed2002

Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2.

The mechanism of heme oxygenase-1 gene (ho-1) activation by heme in immortalized rat proximal tubular epithelial cells was examined. Analysis of the ho-1 promoter identified the heme-responsive sequences as the stress-response element (StRE), multiple copies of which are present in two enhancer regions, E1 and E2. Electrophoretic mobility shift assays identified Nrf2, MafG, ATF3, and Jun and Fos family members as StRE-binding proteins; binding of Nrf2, MafG, and ATF3 was increased in response to heme. Dominant-negative mutants of Nrf2 and Maf, but not of c-Fos and c-Jun, inhibited basal and heme-induced expression of an E1-controlled luciferase gene. Heme did not affect the transcription activity of Nrf2, dimerization between Nrf2 and MafG, or the level of MafG, but did stimulate expression of Nrf2. Heme did not influence the level of Nrf2 mRNA but increased the half-life of Nrf2 protein from approximately 10 min to nearly 110 min. These results indicate that heme promotes stabilization of Nrf2, leading to accumulation of Nrf2. MafG dimers that bind to StREs to activate the ho-1 gene.

Animals↗

PubMed2002

Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium.

Nrf2 mediates inducer-dependent activation of the heme oxygenase-1 (HO-1) gene (Alam, J., Stewart, D., Touchard, C., Boinapally, S., Choi, A. M., and Cook, J. L. (1999) J. Biol. Chem. 274, 26071-26078), but the mechanism by which HO-1 inducers regulate Nrf2 function is not known. Treatment of mouse hepatoma (Hepa) cells with 50 microm CdCl(2) increased the amount of Nrf2 protein in a time-dependent manner; induction was observed within 30 min, prior to the accumulation of HO-1 mRNA. Cadmium did not significantly affect the steady-state level of Nrf2 mRNA or the initial rate of Nrf2 protein synthesis but increased the half-life of Nrf2 from approximately 13 to 100 min. Proteasome inhibitors, but not other protease inhibitors, enhanced the expression of Nrf2, and ubiquitinylated Nrf2 was detected after proteasome inhibition. Cycloheximide inhibited cadmium-stimulated Nrf2 expression and DNA binding activity and attenuated HO-1 mRNA accumulation. Conversely, proteasome inhibitors enhanced HO-1 mRNA and protein accumulation by a Nrf2-dependent mechanism. Together, these results indicate that Nrf2 is targeted for rapid degradation by the ubiquitin-proteasome pathway and that cadmium delays the rate of Nrf2 degradation leading to ho-1 gene activation.

Animals↗

PubMed2002

Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite.

The mechanism of heme oxygenase-1 (ho-1) gene activation by arsenite was examined. Arsenite-stimulated expression of a ho-1 promoter/luciferase chimera in a dose-dependent manner in mouse hepatoma (Hepa) cells. Mutation analyses identified the arsenite-responsive sequence as the stress-response element (StRE), which resembles the binding sites for the AP-1 superfamily of basic-leucine zipper factors. In electrophoretic mobility shift assays, up to seven specific StRE-protein complexes were routinely detected using extracts from untreated Hepa cells whereas a single complex was typically observed after treatment with arsenite. Antibody "supershift" experiments identified Nrf2, JunD, and ATF3 in control complexes and the amount of these factors increased significantly in the arsenite-induced complex. MafG, ATF2, FosB, and JunB were also detected in the arsenite complex. Activation of a StRE-dependent luciferase gene by arsenite was inhibited to varying degrees by dominant-negative mutants of Nrf2, MafK, c-Fos, and CREB but most strongly with the latter. Together, these results implicate multiple basic-leucine zipper transcription factors in ho-1 gene activation by arsenite.

Activating Transcription Factor 2↗

PubMed2002

Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2.

The mechanism of heme oxygenase-1 (ho-1) gene activation by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) was examined. 15d-PGJ(2) stimulated expression of HO-1 mRNA and protein and of a mouse ho-1 gene promoter/luciferase fusion construct (HO15luc) in a dose-dependent manner in mouse hepatoma (Hepa) cells. HO15luc expression was not effected by troglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, but induction by 15d-PGJ(2) was abrogated by the antioxidant N-acetylcysteine. The primary 15d-PGJ(2) responsive sequences were localized to a 5' distal enhancer (E1) and identified as the stress-response element, previously shown to mediate ho-1 activation by several agents, including heme and heavy metals. Treatment of Hepa cells with 15d-PGJ(2) stimulated stress-response element-binding activity as judged by electrophoretic mobility shift assays. Antibody "supershift" experiments identified NF-E2 related factor 2 (Nrf2), but not Fos, Jun, or activating transcription factor/cyclic AMP response element binding protein transcription factors, within the 15d-PGJ(2)-induced complexes. Similarly, a dominant-negative mutant of Nrf2, but not of c-Jun or c-Fos, abrogated 15d-PGJ(2)-stimulated E1 transcription activity. Finally, prior induction of HO-1 in RAW264.7 mouse macrophages by 15d-PGJ(2) attenuated cell death caused by diesel exhaust particle extracts. These results demonstrate that induction of mouse HO-1 expression by 15d-PGJ(2) is independent of PPAR-gamma but dependent on oxidative stress, is regulated by the oxidative stress-activated transcription factor Nrf2, and provides cytoprotective activity.

Animals↗

PubMed2002

Terbinafine in the treatment of Trichophyton tinea capitis: a randomized, double-blind, parallel-group, duration-finding study.

OBJECTIVES: Terbinafine has been shown to be effective in tinea capitis, using different treatment durations. However, no direct comparison of treatment duration has previously been investigated. This randomized, double-blind, parallel-group, multicenter study was designed to assess the effect of terbinafine treatment duration on the outcome of Trichophyton tinea capitis in a North American population. METHODS: A total of 176 patients with a clinical diagnosis of tinea capitis were enrolled in this study and treated with oral terbinafine (3-6 mg/kg/d) for 1, 2, or 4 weeks. All patients were to be followed until week 12. A total of 159 patients had culture-confirmed tinea capitis attributable to Trichophyton species and constituted the intent-to-treat population used for efficacy analysis (50, 55, and 54 patients in the 1-, 2-, and 4-week arms, respectively). RESULTS: At the end of study, effective treatment, defined as negative culture and low scores on signs and symptoms, was achieved in 56%, 69%, and 65% of patients who were treated with terbinafine for 1, 2, and 4 weeks, respectively. A negative culture was achieved in 60%, 76%, and 72%, respectively. Overall, the efficacy data showed that both the 2- and 4-week treatment regimens are clinically superior to the 1-week regimen. Terbinafine was well tolerated, and the incidence of adverse events showed no relationship to the duration of therapy. CONCLUSION: When efficacy, cost, and compliance are taken into consideration, 2 weeks of terbinafine therapy appears to be the optimal treatment duration for patients with Trichophyton tonsurans tinea capitis.

Administration, Oral↗

PubMed2002

Randomized trial evaluating a new 0.5% fluorouracil formulation demonstrates efficacy after 1-, 2-, or 4-week treatment in patients with actinic keratosis.

The efficacy and safety of a new 0.5% fluorouracil topical cream were compared with vehicle control for the treatment of actinic keratosis (AK). Active treatment applied once daily for 1, 2, or 4 weeks was more effective than vehicle control in achieving reduction from baseline in lesion counts and lesion clearance. Active treatment also resulted in significantly better global assessments of overall improvement. Treatment was effective regardless of the number of baseline lesions. Although longer treatment duration correlated with greater efficacy, treatment for 1, 2, or 4 weeks was effective. This new microsphere-based fluorouracil formulation was generally well tolerated; adverse events were primarily limited to facial irritation that resolved quickly after treatment. This new treatment provides a safe alternative to the topical fluorouracil formulations currently available for the 1-, 2-, or 4-week treatment of AK.

Administration, Topical↗