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Biomedical subjects

C E Griffiths

Publications and source records attributed to C E Griffiths.

At least 127 records · Page 7Linked to original sources
PubMed1993

Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients.

BACKGROUND AND METHODS: Irregular disfiguring skin hyperpigmentation due to inflammation may develop in black persons. We investigated the treatment of this hyperpigmentation with topical tretinoin (0.1 percent retinoic acid cream). Fifty-four subjects completed a 40-week randomized, double-blind, vehicle-controlled study. Twenty-four subjects applied tretinoin daily to the face, arms, or both areas, and 30 subjects applied vehicle cream. At base line and after 40 weeks of treatment, each subject's post-inflammatory hyperpigmented lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. RESULTS: The facial post-inflammatory hyperpigmented lesions of the tretinoin-treated subjects were significantly lighter after the 40 weeks of therapy than those of the vehicle-treated subjects (P < 0.001); overall improvement was first noted after four weeks of tretinoin treatment. At the end of treatment, colorimetry demonstrated a 40 percent lightening of the lesions toward normal skin color in the tretinoin-treated lesions, as compared with an 18 percent lightening in vehicle-treated lesions (P = 0.05). The epidermal melanin content in the lesions decreased by 23 percent with tretinoin and by 3 percent with vehicle (P = 0.24). Normal skin was minimally lightened by tretinoin as compared with vehicle, according to both clinical evaluation (0.1 vs. -0.1 unit change on an 8-point scale; P = 0.055) and colorimetry (P < 0.001). Retinoid dermatitis developed in 12 of the 24 tretinoin-treated subjects who completed the study (50 percent) and in 1 tretinoin-treated subject who withdrew from the study, but diminished as the study progressed. CONCLUSIONS: Topical application of tretinoin significantly lightens post-inflammatory hyperpigmentation and, to a clinically minimal but statistically significant degree, lightens normal skin in black persons.

Administration, Cutaneous↗
PubMed1993

CD1 gene expression in human skin.

In human epidermis, expression of CD1a is confined to Langerhans cells (LC), whereas CD1c expression has been observed in dendritic cells of the dermis, as well as the epidermis. In transfected fibroblasts, expression of CD1c at the cell surface appears to exclude expression of either CD1b or CD1a, despite continued transcription of the latter genes. In order to determine whether this mechanism might be operative in human skin, we have compared the expression of CD1a and CD1c on the surface of dermal and epidermal dendritic cells to their expression at the level of mRNA using a combination of dual-label immunofluorescence microscopy, northern blot hybridization, and reverse transcriptase-polymerase chain reaction (RT-PCR). By both immunofluorescence and Northern blotting, CD1c expression was observed in both dermal and epidermal cells, whereas expression of CD1a was confined largely to the epidermis. Moreover, as shown by immunomagnetic bead selection and RT-PCR, CD1a and CD1c were both expressed on epidermal LC, but were absent from other epidermal cell types. These results argue against cell surface exclusion as a mechanism for selective expression of CD1c in human dermis.

Antigens, CD↗
PubMed1993

Comparison of CD271 (adapalene) and all-trans retinoic acid in human skin: dissociation of epidermal effects and CRABP-II mRNA expression.

A new synthetic retinoid analogue, adapalene (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, CD271), which is relatively selective for retinoic acid receptor beta, was noted to be an effective comedolytic agent in the rhino mouse model and to have clinical efficacy against acne. In pursuit of this observation, we studied the effects of CD271 on the development of erythema, spongiosis, and epidermal hyperplasia as well as other well-characterized markers of in vivo retinoid action after 4 d of occluded topical treatment. The objective of the study was to elucidate further those parameters associated with potential clinical efficacy. Twenty-five subjects were treated with 0.1% all-trans retinoic acid cream, all-trans retinoic acid vehicle, 0.1% CD271 gel, or CD271 vehicle under occlusion for 4 d. Only all-trans retinoic acid induced erythema (p < 0.01 versus all other treatments). Similarly, histologic analysis revealed that epidermal hyperplasia and spongiosis were induced only by all-trans retinoic acid (p < 0.01 versus all other treatments). By immunohistochemical analysis: all-trans retinoic acid increased expression of epidermal transglutaminase, involucrin, and calgranulin (p < 0.05 versus all other treatments). In contrast to these data, both CD271 and all-trans retinoic acid caused marked and significant (p < 0.05) elevation of cellular retinoic acid-binding protein-II (CRABP-II) messenger ribonucleic acid steady-state levels as judged by quantitative RNA blot analysis. Although CD271 treatment did not lead to erythema or affect epidermal morphology, its ability to induce a marker of retinoid action (i.e., CRABP-II) was 70% the potency of all-trans retinoic acid. This study suggests that CRABP-II gene expression may be a more sensitive indicator of retinoid biologic activity in skin than are erythema or changes in epidermal morphology and differentiation.

Adapalene↗
PubMed1993

Differential expression of protein kinase C isoenzymes in normal and psoriatic adult human skin: reduced expression of protein kinase C-beta II in psoriasis.

Psoriatic lesions contain elevated levels of 1,2-diacylglycerol, the physiologic activator of protein kinase C (PKC), suggesting that PKC activation may be aberrant in psoriasis. We therefore have investigated the expression and properties of PKC isozymes in normal and psoriatic skin and in human skin cells. Chromatographic and immunoblot analyses revealed the presence of the calcium-dependent PKC isozymes PKC-alpha and -beta, but not -gamma, in normal human epidermis. PKC-beta was more prominent, constituting two thirds of the total calcium-dependent PKC activity. In psoriatic lesions, expression of both PKC-alpha and -beta was decreased, with preferential reduction (80%) of PKC-beta. Northern analysis and semi-quantitative polymerase chain reaction (PCR) indicated no change in the mRNA levels of PKC-alpha and -beta between normal and psoriatic epidermis. In normal epidermis, PKC-alpha was expressed mainly in the lower epidermis, whereas PKC-beta was localized to the upper cell layers, with very intense staining of CD1a+ Langerhans cells. In psoriasis, PKC-alpha staining was present in the lower epidermis, whereas PKC-beta staining was essentially absent, with the exception of some positive inflammatory cells. In addition to PKC-alpha and beta, immunoblot and Northern/PCR analysis revealed expression of four calcium-independent PKC isozymes, delta, epsilon, zeta, and eta, in both normal and psoriatic skin. There were no significant differences in mRNA levels among any of these PKC isozymes, between normal and psoriatic skin. Soluble PKC-zeta protein was modestly increased (twofold) in psoriatic, compared to normal, skin, whereas the levels of PKC-delta, epsilon, and eta were unchanged. Analysis of PKC isozyme expression in the three major cell types of human epidermis revealed that Langerhans cells and keratinocytes were the major sources of PKC-beta and PKC-zeta, respectively. These data demonstrate the diversity of PKC isozyme expression in human skin, and suggest that alterations of PKC-beta and -zeta may participate in the aberrant regulation of growth and differentiation observed in psoriasis.

Adult↗
PubMed1993

Stimulus-selective induction of CRABP-II mRNA: a marker for retinoic acid action in human skin.

Acute topical treatment of human skin with retinoic acid (RA) results in a pleiotropic response, some aspects of which are mimicked by non-specific irritants. To identify reliable cutaneous markers of retinoid action, it is important to determine which aspects of this response are specifically due to the presence of RA. We have previously demonstrated a rapid and pronounced increase in steady-state cellular RA-binding protein II (CRABP-II)mRNA levels after topical RA treatment. Here we characterize the dose dependence and kinetics of this response, and compare the effects of a well-known irritant, sodium dodecylsulfate (SDS), to those of RA and its vehicle. The induction of CRABP-II mRNA in response to 0.1% RA cream was maximal by 16 h (elevenfold relative to untreated skin), and persisted at near-maximal levels (eight-fold) for up to 4 d. RA was potent in eliciting this response, as approximately half-maximal stimulation was observed after 16 h of treatment with 0.001% RA. Treatment for 4 d with 0.1% RA cream versus 2% SDS in RA vehicle resulted in nearly identical levels of cutaneous erythema, spongiosis, and epidermal thickening. However, the CRABP-II mRNA response to 2% SDS was no greater than that observed in response to vehicle alone (2.9 times relative to occluded skin control at 4 d). SDS also had no effect upon either CRABP-II or RAR-beta mRNA levels in quiescent human dermal fibroblasts in vitro, whereas RA elicited both responses at 1000-times lower concentrations than SDS. Taken together, these data identify the CRABP-II mRNA response as a reliable, rapid, and selective marker for retinoid activity in human skin.

Carrier Proteins↗
PubMed1993

Differential regulation of tyrosinase activity in skin of white and black individuals in vivo by topical retinoic acid.

Tyrosinase activity is a key determinant of melanin production in skin. Because retinoic acid regulates tyrosinase activity in melanoma cells, we analyzed modulation of pigmentation in vivo by retinoic acid. Black and white subjects were either not treated, or treated topically for 4 d under occlusion with vehicle, retinoic acid (0.1%), or the irritant sodium lauryl sulfate (2%). In untreated skin, tyrosinase activity and melanin content were significantly greater (2.3 times, and 3.2 times, respectively) in blacks versus whites. Four days of treatment with topical retinoic acid did not alter tyrosinase activity or melanin content in black skin. In contrast, retinoic acid treatment significantly induced (2.7 times, n = 8) tyrosinase activity, compared to vehicle treatment, in white skin. Melanin content, however, remained unchanged at 4 d. In separate experiments, tyrosinase activity in white subjects (n = 25) was increased 16% (p = 0.01) in sodium lauryl sulfate-treated skin, and 77% (p = 0.0005) in retinoic acid-treated skin, compared to vehicle-treated skin. The effect of retinoic acid on tyrosinase activity could be differentiated from non-specific irritation, because tyrosinase activity in retinoic acid-treated skin was significantly greater (52%, p = 0.004) than sodium lauryl sulfate-treated skin. Similar results were obtained with the dihydroxyphenylalanine reaction done on vehicle, sodium lauryl sulfate-, and retinoic acid-treated white skin. Northern analysis (n = 6) and semi-quantitative polymerase chain reaction (n = 6) demonstrated that retinoic acid treatment did not alter tyrosinase mRNA levels in white skin. Western analysis revealed that induction of tyrosinase activity by retinoic acid also was not associated with increased tyrosinase protein content (n = 9), indicating that regulation of tyrosinase activity by retinoic acid occurs through a post-translational mechanism. These data demonstrate that low tyrosinase activity in white skin in vivo is retinoic acid inducible and high tyrosinase activity in black skin in vivo is neither further induced nor reduced by retinoic acid.

Administration, Topical↗
PubMed1993

An in vivo experimental model for effects of topical retinoic acid in human skin.

An occlusive patch-test assay has been developed for assessment of topical retinoid action in human epidermis. Previous work with this assay has demonstrated marked epidermal hyperplasia in skin treated with topical all-trans-retinoic acid for 4 days and similar effects with the local irritant, sodium lauryl sulphate. To investigate the capabilities of this assay further, a time-course and dose-response were performed with all-trans-retinoic acid, and a comparison made with sodium lauryl sulphate. At no time, between 1 and 4 days, could the clinical or histological effects of 0.1% and 0.025% cream formulations of all-trans-retinoic acid be distinguished from each other. Epidermal hyperplasia was used to generate a 4-day dose-response for all-trans-retinoic acid at concentrations from 0.001 to 0.025% dissolved in a 70% ethanol/30% propylene glycol vehicle. All-trans-retinoic acid could be successfully differentiated from sodium lauryl sulphate at 2 days by virtue of its greater ability to increase epidermal thickness, spongiosis and glycosaminoglycan deposition. It appears that although all-trans-retinoic acid and sodium lauryl sulphate produce similar epidermal histological changes at 4 days, significant differences at earlier time-points suggest differing mechanisms of action. In addition, this in vivo human assay is able to provide potency ranking for doses of all-trans-retinoic acid, and may predict clinical efficacy of retinoids in improvement of acne and/or photodamage.

Administration, Topical↗
PubMed1993

Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial.

Melasma is a common disorder of cutaneous hyperpigmentation predominantly affecting the faces of women. Little is known about the aetiology of melasma, and treatment is frequently disappointing. Topical tretinoin is of benefit in treating other forms of hyperpigmentation, for example liver spots, and we therefore investigated its effectiveness in melasma. Thirty-eight women completed a randomized, vehicle-controlled study, in which they applied 0.1% tretinoin (n = 19) or vehicle cream (n = 19) once daily to the face for 40 weeks. At the end of treatment 13 (68%) of 19 tretinoin-treated patients were clinically rated as improved or much improved, compared with 1 (5%) of 19 in the vehicle group (P = 0.0006). Significant improvement first occurred after 24 weeks of tretinoin treatment. Colorimetry (an objective measure of skin colour) demonstrated a 0.9 unit lightening of tretinoin-treated melasma and a 0.3 unit darkening with vehicle (P = 0.01); these results correlated with clinical lightening (r = 0.55, P = 0.0005). Histologically, epidermal pigment was reduced 36% following tretinoin treatment, compared with a 50% increase with vehicle (P = 0.002). Reduction in epidermal pigment also correlated with clinical lightening (r = -0.41, P = 0.01). Moderate cutaneous side-effects of erythema and desquamation occurred in 88% of tretinoin-treated and 29% of vehicle-treated patients. Topical 0.1% tretinoin produces significant clinical improvement of melasma, mainly due to reduction in epidermal pigment, but improvement is slow.

Administration, Topical↗
PubMed1993

Inflammatory breast carcinoma (carcinoma erysipeloides): an easily overlooked diagnosis.

A 70-year-old woman developed erythema and induration of the right chest wall, and swelling of her right arm. The provisional diagnosis was deep venous thrombosis and/or cellulitis of the right arm. Skin biopsy showed a poorly differentiated adenocarcinoma within lymphatic vessels, and immunohistochemical staining revealed this to be of breast origin. Inflammatory carcinoma or carcinoma erysipeloides represents < 1% of all cases of breast carcinoma. Our case illustrates the importance of considering this entity in the differential diagnosis of unilateral chest wall erythema and induration.

Aged↗
PubMed1993

Topical retinoic acid for photoaging: clinical response and underlying mechanisms.

Photoaging is primarily composed of wrinkling, mottled hyperpigmentation and a tactile roughness of the skin, all three of these parameters improve following use of topical retinoids. It appears that smoothening of the skin results from a combination of epidermal changes including thickening, stratum corneum compaction and glycosaminoglycan deposition. Lightening of actinic lentigines and mottled hyperpigmentation correlates with a reduction in epidermal melanin content maybe resulting from inhibition of tyrosinase activity. Effacement of wrinkling in mice correlates with new collagen synthesis, and there is evidence that this is also the case in humans. An irritant dermatitis is a feature of retinoid-treated skin but this diminishes in severity during treatment despite continued improvement in photoaging. Thus it is unlikely that irritation per se is responsible for clinical improvement.

Administration, Topical↗
PubMed1993

Retinoic acid metabolites exhibit biological activity in human keratinocytes, mouse melanoma cells and hairless mouse skin in vivo.

Topical all-trans retinoic acid (RA) modulates growth and differentiation of skin and is used in the treatment of various dermatological disorders. RA is metabolized to 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, which are believed to be markedly less active than RA. 3,4-didehydroretinoic acid (ddRA) is a metabolite of 3,4-didehydroretinol which is present in skin. ddRA is biologically active and acts as a morphogen. We have determined the relative biological activity of ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA as assessed by three retinoid responsive systems relevant to skin. RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA (10-100 nM) reduced epidermal transglutaminase activity in human keratinocytes to similar extents, and inhibited alpha-melanocyte-stimulating hormone-isobutylmethylxanthine-inducible tyrosinase activity in Cloudman S-91 mouse melanoma cells by 67, 39, 48, 51 and 19%, respectively, at 100 nM. Daily topical application of the retinoids to hairless mouse skin for 4 days resulted in dose-dependent changes in epidermal thickness and global histological score. The relative potencies of RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, as calculated by parallel line assay, were 1.0, 0.60, 0.34, 0.29 and 0.18, respectively, for epidermal hyperplasia and 1.0, 0.78, 0.23, 0.14 and 0.08, respectively, for global histological score. Interestingly, the compounds exhibited a similar rank order of potency with respect to induction of cellular retinoic acid binding protein-II mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Paraneoplastic pemphigus presenting as a lichen planus pemphigoides-like eruption.

BACKGROUND: Paraneoplastic pemphigus refers to a specific disease entity in which neoplasia is associated with severe mucosal ulceration and polymorphous cutaneous eruptions, sometimes resembling erythema multiforme. Direct immunofluorescence and indirect immunofluorescence on standard substrates are similar to pemphigus vulgaris; however, paraneoplastic pemphigus serum uniquely binds to all epithelia and has distinctive immunoprecipitation characteristics. OBSERVATIONS: A 63-year-old woman with chronic lymphocytic leukemia developed a severe, mucocutaneous, vesiculobullous eruption with the clinical and histopathologic characteristics of lichen planus pemphigoides evolving into a Stevens-Johnson-like presentation and the immunofluorescence findings of pemphigus vulgaris. Evaluation of her serum confirmed the presence of autoantibodies specific for paraneoplastic pemphigus by indirect immunofluorescence and immunoprecipitation criteria. CONCLUSION: The spectrum of paraneoplastic pemphigus must now be expanded to include cases that present clinically and histologically as a lichen planus pemphigoides-like eruption.

Diagnosis, Differential↗
PubMed1993

Effects of all-trans retinoic acid and Ca++ on human skin in organ culture.

In this study, we have established an organ culture model of human skin and examined the effects of both all-trans retinoic acid (RA) and extracellular Ca++ on the epidermal and dermal components of the organ-cultured skin. Our data show that while organ cultures maintained in serum-free, growth factor-free culture medium containing 0.15 mM Ca++ degenerated rapidly, those treated with concentrations of RA that have been shown previously to stimulate fibroblast and keratinocyte proliferation in monolayer culture (J Invest Dermatol 1989, 93:449; 1990, 94:717; Am J Pathol 1990, 136:1275) demonstrated a healthy appearance for up to 12 days. Degeneration of the control cultures was characterized by separation of the epidermis from the underlying dermis, progressive cell necrosis leading to a complete absence of viable cells from both the dermal and epidermal compartments, disintegration and fibrillation of the dermal connective tissue, and a cessation of protein synthesis. RA-treated organ cultures contained large numbers of healthy-appearing cells in both the epidermal and dermal compartments. One or several layers of viable basal cells in the epidermis could be seen at least through day 12. However, the upper layers of the epidermis frequently separated from the cells in the basal layer. The dermal connective tissue was histologically well-preserved. Furthermore, the level of protein synthesis was higher in the RA-treated cultures than in the control cultures. In addition to treating organ cultures with RA, other cultures were exposed to serum-free, growth factor-free culture medium containing 1.4 mM Ca++. The presence of the elevated Ca++ concentration also preserved cellular and connective tissue structures in the dermal and epidermal compartments. In comparison to RA there was better preservation of the overall epidermal structure. The upper layers of epidermal cells did not separate from the basal cells, and the various stages of epithelial differentiation could be seen. Histologically, the dermis was well-preserved in the presence of elevated extracellular Ca++. Specimens treated with a combination of Ca++ and RA demonstrated features consistent with the features induced by each treatment separately. This included an expanded basal layer of epithelial cells and a prominent keratotic layer with a fairly orderly pattern of differentiation. The tendency of the upper epidermis to separate from the basal cells was partially mitigated. Taken together, these data indicate that both RA and extracellular Ca++ act to prevent the degeneration of human skin in organ culture but probably do so through different mechanisms.

Adult↗
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↗