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Biomedical subjects

C E Griffiths

Publications and source records attributed to C E Griffiths.

At least 19 recordsLinked to original sources
PubMed1992

Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage.

BACKGROUND: The hyperpigmented lesions commonly called liver spots distress patients, in part because such lesions are associated with aging. We investigated their treatment with topical 0.1 percent tretinoin (retinoic acid). METHODS: Fifty-eight patients completed a 10-month randomized, double-blind study in which they applied either 0.1 percent tretinoin (n = 28) or vehicle (n = 30) cream daily to the face, upper extremities, or both. Fifteen patients who responded well were than randomly assigned to continue tretinoin therapy or use vehicle alone for six more months. Patients were evaluated by physical examination every month and by analysis of biopsy specimens of lesions obtained at base line and at the end of the 10-month trial. RESULTS: After one month of treatment the patients treated with tretinoin had significant lightening of hyperpigmented lesions as compared with the patients who received vehicle (P less than 0.002). After 10 months, 20 (83 percent) of the 24 patients with facial lesions who were treated with tretinoin had lightening of these lesions, as compared with 8 (29 percent) of the 28 patients with facial lesions who received vehicle. The results for lesions of the upper extremities were similar. As compared with vehicle, tretinoin caused a significant decrease in the degree of epidermal pigmentation and increases in the degree of compaction of stratum corneum, thickness of the granular cell layer, and epidermal thickness. Reductions in epidermal pigmentation evident on histologic analysis were significantly correlated with the degree of clinical lightening of lesions (r = -0.53, P less than 0.0001). During the 6-month follow-up study, specifically identified lesions that had disappeared during the first 10 months of tretinoin treatment did not return in any patient, and six of seven patients who continued to use tretinoin had further improvement. CONCLUSIONS: Topical 0.1 percent tretinoin significantly improves both clinical and microscopical manifestations of liver spots; these lesions do not return for at least six months after therapy is discontinued.

Administration, Topical↗
PubMed1992

Intralesional cyclosporine for psoriasis. Relationship of dose, tissue levels, and efficacy.

UNLABELLED: BACKGROUND AND DESIGN--To avoid systemic side effects, topical and intralesional administration of cyclosporine has been used; however, only intralesional administration has been successful. To understand more about the dosing requirements and resultant tissue levels of intralesional cyclosporine, we injected psoriasis plaques in a double-blind fashion with three different concentrations of cyclosporine (17 mg/mL in seven patients, 10 mg/mL in 13 patients, and 2.5 mg/mL in 11 patients) or matching vehicle three times weekly for 4 weeks. RESULTS--Statistically significant improvement was observed in plaques treated with 17 mg/mL (P = .003) compared with vehicle-treated plaques; the improvements in plaques treated with 10 mg/mL (P = .078) and 2.5 mg/mL (P = .054) achieved marginal statistical significance compared with vehicle treatment. Four weeks after discontinuation of therapy, the change from pretherapy in plaques that had received 17 mg/mL of cyclosporine was statistically significantly better (P less than .0001) than that with vehicle treatment. A similar finding but of marginal statistical significance (P = .059) occurred in the plaques that had received 10 mg/mL of cyclosporine. Throughout the study, untreated psoriasis plaques did not improve. Transient pain was the most common side effect noted with both cyclosporine and vehicle injections. Tissue levels of cyclosporine tended to be highest in plaques receiving the 17-mg/mL concentration; blood levels of cyclosporine were low throughout the study. CONCLUSIONS: --Intralesional cyclosporine requires a sufficient dosage to improve psoriasis, apparently by a local mechanism of action. Improvement may persist for 4 weeks or longer.

Cyclosporine↗
PubMed1992

Failure of reticular erythematous mucinosis to respond to cyclosporine.

We describe a 48-year-old woman who had worsening psoriasis, photosensitive reticular erythematous mucinosis (REM), and acne rosacea. The psoriasis was unresponsive to etretinate, and the REM was unsuccessfully treated with hydroxychloroquine. Cyclosporine (6 mg/kg/day) successfully cleared the psoriasis in 8 weeks but did not improve the REM and acne rosacea. Possible causes for the lack of response of the REM to cyclosporine are discussed.

Cyclosporine↗
PubMed1992

Differential modulation of transforming growth factor-beta 1 expression and mucin deposition by retinoic acid and sodium lauryl sulfate in human skin.

Immunohistochemical staining of skin sections with two polyclonal antibodies (anti-CC 1-30 and anti-LC 1-30), specific for transforming growth factor-beta 1, revealed increased extracellular and decreased intracellular expression of transforming growth factor-beta 1 in retinoic acid-treated, compared to vehicle-treated, skin. Transforming growth factor-beta 1 staining, with both antibodies, was most marked in the upper layers of the epidermis, although dermal staining was also evident. The modulation of transforming growth factor-beta 1 expression by retinoic acid occurred in the absence of any change in its mRNA level. Transforming growth factor-beta 1 protein, as detected by rabbit polyclonal antibody (anti-LC 50-75) and mRNA, were only minimally detected in either retinoic acid- or vehicle-treated skin. Similar changes in TGF-beta 1 and TGF-beta 2 immunoreactivity and mRNA levels, as observed in retinoic acid-treated skin, were observed in skin following topical application of the irritant sodium lauryl sulfate, indicating that the alterations induced by retinoic acid were not specific. In contrast, mucin deposition, which is induced by transforming growth factor-beta, was elevated in retinoic acid-treated but not sodium lauryl sulfate-treated skin. Cultured adult human keratinocytes also expressed predominantly transforming growth factor-beta 1 protein, as measured by ELISA, and mRNA. Treatment of keratinocytes with retinoic acid resulted in a 50% induction of transforming growth factor-beta 1 protein, without any detectable change in transforming growth factor-beta 2. These data demonstrate disassociation of modulation of transforming growth factor-beta 1 expression and mucin deposition by retinoic acid and sodium lauryl sulfate in human skin in vivo. Whereas alterations in transforming growth factor-beta 1 expression were observed in both retinoic acid- and sodium lauryl sulfate-treated skin, accumulation of mucin was specific to retinoic acid-treated skin.

Adult↗
PubMed1992

Acute or chronic topical retinoic acid treatment of human skin in vivo alters the expression of epidermal transglutaminase, loricrin, involucrin, filaggrin, and keratins 6 and 13 but not keratins 1, 10, and 14.

Histologic and immunocytochemical analyses were performed on cutaneous biopsies from 10 patients treated with retinoic acid under occlusion for 4 d compared to biopsies from 19 patients treated nightly for 16 weeks. Acute application of RA caused epidermal thickening (9 of 10 samples), stratum granulosum thickening (7 of 10), parakeratosis (4 of 10), a marked increase in the number of cell layers expressing epidermal transglutaminase (7 of 10), and focal expression of two non-epidermal keratins, K6 (8 of 10) and K13 (2 of 10), changes also observed with chronic treatment. Involucrin, filaggrin, and loricrin were also altered in samples from both acute and chronic treatment. An increased number of cell layers expressed both involucrin and filaggrin from both the acute (7 of 10) and chronic (14 of 19) treatment groups. In the acute group, loricrin expression was significantly reduced or absent in some regions of the epidermis (5 of 10), whereas most chronic samples showed an increased number of cell layers expressing loricrin (12 of 19). The pattern of expression of three major epidermal differentiation products, keratins K1, K10, and K14, was not significantly altered in any of the acute or chronic samples, although there was a slight reduction in the detection of K10 in two of the acute samples. Thus, acute topical RA treatment under occlusion caused substantial changes in the epidermis, and reproduced most, but not all of the effects of chronic treatment.

Administration, Topical↗
PubMed1992

Differential regulation of retinoic acid receptors and binding proteins in human skin.

Many of the pleiotropic effects of retinoids are likely to be mediated by nuclear retinoic acid receptors (RAR) acting as ligand-dependent enhancer factors. However, in previous studies we have been unable to document altered RAR expression at the RNA level in response to retinoic acid (RA) treatment or in psoriatic lesions, conditions characterized by marked alterations in keratinocyte proliferation and differentiation, which are either caused by or responsive to RA. In an attempt to identify other potential regulators of RA responsiveness, we have used RNA blot hybridization to study the expression of the cellular retinoic acid binding proteins (CRABP) CRABP-I and CRABP-II, the RAR-gamma isoforms RAR-gamma 1 and RAR-gamma 2, and the low-affinity RAR homologue RXR in normal, RA-treated, and psoriatic human epidermis. CRABP-II is selectively and markedly induced by RA in adult human skin (J Biol Chem 266:17662-17666, 1991). However, in submerged, serum-free keratinocyte cultures, CRABP-II mRNA could not be induced by RA. Comparisons of intact human skin, submerged keratinocyte cultures, and human skin equivalent cultures indicated that induction of CRABP-II by RA requires epidermal stratification, dermal-epidermal interactions, or both. CRABP-II transcripts were also expressed in heat-separated human dermis at levels similar to those found in epidermal keratome biopsies, whereas CRABP-I transcripts were undetectable in dermal RNA. CRABP-II transcripts were markedly elevated in psoriatic lesions, as they were in RA-treated skin. In contrast, CRABP-I mRNA was undetectable and not increased in psoriatic lesions. Expression of RAR-gamma isoforms and RXR was not detectably altered in either psoriatic lesions or in RA-treated skin. Thus, altered expression of CRABP-II appears more likely to regulate the cutaneous actions of RA than does altered expression of CRABP-I, RXR, or RAR-gamma isoforms. From these and other results, a model for regulation of RA action involving sequestration of RA by CRABP-II is proposed.

Base Sequence↗
PubMed1992

Short-term retinoic acid treatment increases in vivo, but decreases in vitro, epidermal transglutaminase-K enzyme activity and immunoreactivity.

Epidermal transglutaminase-K is believed to catalyze the covalent linking of loricrin and involucrin to form cross-linked (CE) envelopes. In normal skin, transglutaminase-K is expressed as a band immediately below the stratum corneum, whereas in psoriasis and healing skin its expression is considerably expanded throughout the suprabasal layers. We have investigated whether the hyperproliferative state induced by short-term application of topical retinoic acid is similarly characterized by an increase in transglutaminase-K enzyme activity and immunoreactivity. Retinoic acid (0.1% cream) or vehicle were applied to human skin and occluded for 4 d. Skin biopsies were obtained for measurement of transglutaminase-K and transglutaminase-C activity and immunoreactivity. For comparison, cultured normal human keratinocytes were incubated for 4 d in the presence of 1 microM retinoic acid and the subsequent transglutaminase-K activity and immunoreactivity measured. Transglutaminase-K activity was increased 2.8 times in retinoic acid compared to vehicle-treated skin (p less than 0.005, n = 12) whereas there was no significant difference in transglutaminase-C activity. However, transglutaminase-K mRNA levels were not significantly different between retinoic acid- and vehicle-treated skin. In vehicle-treated skin, transglutaminase-K immunoreactivity was limited to a narrow, substratum corneal band, but was considerably expanded in a diffuse suprabasal pattern in retinoic acid-treated epidermis. In contrast, transglutaminase-K immunostaining was decreased and its enzymatic activity reduced sixfold in retinoic acid-treated keratinocytes (p less than 0.01, n = 4). These results demonstrate that retinoic acid treatment in vivo, in contrast to in vitro, leads to not only increased transglutaminase-K protein expression but also increased enzymatic activity in the absence of detectable increases in mRNA levels. These data, taken with the previously reported lack of in vivo modulation of the differentiation markers keratins 1 and 10 by retinoic acid, indicate that certain aspects of keratinocyte terminal differentiation that are altered in vitro by retinoic acid do not occur in vivo in human skin.

Cells, Cultured↗
PubMed1992

Expression of growth hormone receptor, insulin-like growth factor 1 (IGF-1) and IGF-1 receptor mRNA and proteins in human skin.

A cDNA corresponding to the membrane receptor for growth hormone (GH) was amplified by polymerase chain reaction (PCR) directly from human skin. The cDNA was cloned and found to have complete sequence homology to the extracellular domain of human liver GH receptor (GH-R). Northern analysis, using the cloned GH-R as probe, revealed relatively higher levels of GH-R transcripts in cultured human dermal fibroblasts compared to cultured keratinocytes or keratome biopsies. Semi-quantitative PCR analysis indicated that the level of GH-R mRNA in cultured melanocytes was similar to that in fibroblasts. The receptor protein encoded by GH-R mRNA in fibroblasts was shown by affinity cross-linking to have an apparent M(r) of 115-120 kDa, similar to that of 3T3-F442A fibroblasts used as a control. mRNA transcripts for the major mediator of GH actions, insulin-like growth factor 1 (IGF-1), were detected by PCR in fibroblasts, melanocytes, and keratome biopsies, but not in keratinocytes. In contrast, IGF-1 receptor mRNA were abundant in cultured keratinocytes and skin biopsies, as determined by Northern analysis. IGF-1 but not GH (5-50 ng/ml) promoted clonal proliferation of cultured keratinocytes. In contrast, GH (10 ng/ml) after 5 d markedly increased fibroblast cell numbers (70%, p less than 0.009) over 0.2% serum control. These data indicate that human skin cells possess the molecular elements necessary to respond to GH and raise the possibility that GH may influence skin growth in vivo.

Base Sequence↗
PubMed1992

Cellular localization of mRNA for cellular retinoic acid-binding protein II and nuclear retinoic acid receptor-gamma 1 in retinoic acid-treated human skin.

We have previously shown that cellular retinoic acid-binding protein II (CRABP-II), but not cellular retinoic acid-binding protein I (CRABP-I), mRNA expression is markedly induced in human skin by topical retinoic acid. In the present study, we have investigated the pattern of expression of CRABP-II transcripts in 4-d RA-treated human skin by non-radioactive in situ hybridization (n = 5) and Northern analysis (n = 4). RA induced accumulation of CRABP-II transcripts throughout the epidermis, dermal fibroblasts, and endothelial cells as determined by in situ hybridization. In skin treated with vehicle, a faint hybridization signal was observed only in basal layers of the epidermis consistent with low-level expression of CRABP-II mRNA. RA-mediated accumulation of CRABP-II transcripts in skin was also confirmed by Northern analysis. Neither RA nor vehicle induced significant changes in nuclear RA receptor-gamma 1 or keratin 5 gene expression in skin as determined by in situ or Northern hybridization. These results indicate that RA-induced CRABP-II mRNA accumulation is primarily localized to spinous and granular layers in epidermis, and in superficial dermis.

Administration, Topical↗
PubMed1992

Mechanisms of action of retinoic acid in skin repair.

The ability of topically applied retinoic acid to improve photoaged skin has stimulated research interest into its mechanism of action. Currently available assay systems are either in-vitro or mouse models, neither of which are truly representative of the in-vivo situation in man. Another drawback is that skin biopsies available from studies using retinoic acid to treat photoageing are of insufficient size to accomplish biochemical and molecular assays. In order to address these problems, a 4-day in-vivo retinoid assay has been developed which serves as a good predictive model for the chronic effects of retinoic acid on skin and helps to characterize the mechanism of action of retinoic acid.

Carrier Proteins↗
PubMed1992

The clinical identification and quantification of photodamage.

The distinction between intrinsic and extrinsic ageing can be made on both histological and clinical grounds. Clinical criteria associated with the diagnosis of extrinsic ageing are coarse wrinkles, actinic lentigines, elastotic conditions, purpura, telangiectasia and cutaneous neoplasms. These parameters are always superimposed on changes associated with intrinsic ageing: namely, fine wrinkles and benign growths. There is heightened interest in extrinsic ageing as a result of studies demonstrating the efficacy of topical tretinoin in improving this condition. As a consequence, systems for grading extrinsic ageing have been developed, including a photographic standard scale which removes some of the subjectivity inherent to current methodology.

Adult↗
PubMed1992

Human skin levels of retinoic acid and cytochrome P-450-derived 4-hydroxyretinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor-mediated transcription in vitro.

Metabolism of retinoic acid to a less active metabolite, 4-hydroxyretinoic acid, occurs via cytochrome P-450 isozyme(s). Effect of a pharmacological dose of retinoic acid on the level of retinoic acid in skin and on cytochrome P-450 activity was investigated. A cream containing 0.1% retinoic acid or cream alone was applied topically to adult human skin for four days under occlusion. Treated areas were removed by a keratome and a microsomal fraction was isolated from each biopsy. In vitro incubation of 3H-retinoic acid with microsomes from in vivo retinoic acid treated sites resulted in a 4.5-fold increase (P = 0.0001, n = 13) in its transformation to 4-hydroxyretinoic acid in comparison to in vitro incubations with microsomes from in vivo cream alone treated sites. This cytochrome P-450 mediated activity was oxygen- and NADPH-dependent and was inhibited 68% by 5 microM ketoconazole (P = 0.0035, n = 8) and 51% by carbon monoxide (P = 0.02, n = 6). Cotransfection of individual retinoic acid receptors (RARs) or retinoid X receptor-alpha (RXR-alpha) and a chloramphenicol acetyl transferase (CAT) reporter plasmid containing a retinoic acid responsive element into CV-1 cells was used to determine the ED50 values for stimulation of CAT activity by retinoic acid and its metabolites. Levels of all trans and 13-cis RA in RA-treated tissues were greater than the ED50 values determined for all three RARs with these compounds. Furthermore, the level of all trans RA was greater than the ED50 for RXR-alpha whereas the 4-OH RA level was greater than the ED50 for RAR-beta and RAR-gamma but less than for RAR-alpha and RXR-alpha. These data suggest that there are sufficient amounts of retinoic acid in treated skin to activate gene transcription over both RARs and RXR-alpha.

Administration, Topical↗
PubMed1992

Treatment of pyoderma gangrenosum with cyclosporine.

BACKGROUND AND DESIGN: Pyoderma gangrenosum is a chronic inflammatory ulcerative skin disease of unknown origin, often associated with various diseases including inflammatory bowel disease, inflammatory arthritis, monoclonal gammopathies, hepatitis, and myeloproliferative disorders. Treatment of associated systemic disorders may improve the ulcers, but lesions may be recalcitrant and persist for months to years. Therapy for pyoderma gangrenosum includes high-dose systemic corticosteroids, sulfa drugs such as sulfasalazine, clofazimine, and immunosuppressive agents such as mercaptopurine and azathioprine; these drugs are sometimes ineffective. RESULTS: We present a series of 11 patients with pyoderma gangrenosum, with a wide range of underlying diseases, whose ulcers were refractory to usual therapy and who were treated with low-dose cyclosporine. Ten of the 11 patients cleared rapidly and completely with cyclosporine therapy. CONCLUSIONS: Cyclosporine should be seriously considered as a primary form of treatment for pyoderma gangrenosum.

Adult↗
PubMed1992

A photonumeric scale for the assessment of cutaneous photodamage.

BACKGROUND AND DESIGN: The assessment of the severity of cutaneous photodamage and its response to treatment is an impractical consideration for most practitioners without extensive experience or recourse to high-quality, standardized, baseline photographs. To address this problem, a nine-point photonumeric standard scale was developed using photographs of subjects representing grades of photodamage from none to severe. This scale was formally tested in a side-by-side comparison with a conventional and widely used written descriptive scale. A panel of seven graders used both scales to score two sets of 25 photographs of photodamaged individuals, and the intergrader agreement and repeatability for the scales were calculated. RESULTS: The photonumeric scale demonstrated significantly greater agreement between graders than did the descriptive scale (chance-corrected agreements of 0.31 and 0.11, respectively, P less than .0001) with no significant difference in repeatability between the two methods. CONCLUSIONS: This study demonstrates that the photonumeric standard scale is superior to existing methodology in the accurate assessment of cutaneous photodamage and would be a useful adjunct to studies of the efficacy of skin repair agents for this indication.

Humans↗
PubMed1991

Keratinocytes as initiators of inflammation.

Environmental stimuli responsible for inducing cutaneous inflammation include contact allergens and ultraviolet light. We postulate that these diverse stimuli trigger a cutaneous inflammatory response by directly inducing epidermal keratinocytes to elaborate specific pro-inflammatory cytokines and adhesion molecules. The consequences are activation of dermal microvascular endothelial cells and selective accumulation of specific mononuclear cells in the dermis and epidermis. Thus, keratinocytes may act as "signal transducers", capable of converting exogenous stimuli into the production of cytokines, adhesion molecules, and chemotactic factors (acting in an autocrine and paracrine fashion) responsible for initiation of "antigen-independent" cutaneous inflammation. The initiation phase may facilitate or promote an amplification phase with additional production of tumour-necrosis factor alpha and interferon gamma via an "antigen-dependent" pathway, and keratinocyte/T cell/antigen-presenting dendritic cellular associations. The direct activation of keratinocytes, with their ability to produce the complete repertoire of pro-inflammatory cytokines, can profoundly influence endogenous and recruited immunocompetent cells, thereby providing the critical trigger responsible for the swift and clinically dramatic alterations that occur following contact between the epidermis and a host of "noxious" agents.

Catechols↗