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Biomedical subjects

D M Carter

Publications and source records attributed to D M Carter.

At least 19 recordsLinked to original sources
PubMed1992

Lack of efficacy of phenytoin in recessive dystrophic epidermolysis bullosa. Epidermolysis Bullosa Study Group.

BACKGROUND: Recessive dystrophic epidermolysis bullosa is an uncommon, severely disabling, heritable disorder characterized by abnormal fragility of the skin. Open trials have suggested that phenytoin is an effective treatment, and this therapy is now widely used. METHODS: To determine the efficacy of phenytoin in the treatment of recessive dystrophic epidermolysis bullosa, we performed a randomized, double-blind, placebo-controlled, crossover trial in 36 patients. Each treatment was given for five to seven months, separated by a two-month period. We measured the total number of blisters and erosions on the entire body, the size of three plaques containing blisters and erosions, and the number of blisters and erosions in the three plaques at the beginning and end of each treatment period in each patient. RESULTS: Twenty-two patients completed both courses of therapy, seven patients completed one course, and seven patients withdrew before completing a single course. There was no significant difference in disease activity between phenytoin treatment and placebo treatment, as measured by changes in the number of blisters and erosions on the entire body (7 percent decrease vs. 6 percent increase), in the area of three designated plaques (0.4 percent decrease vs. 0.2 percent increase), or in the number of blisters and erosions in the designated plaques (12 percent decrease vs. 31 percent increase). CONCLUSIONS: Phenytoin is not an effective treatment for patients with recessive dystrophic epidermolysis bullosa.

Adolescent↗
PubMed1992

The insulin-like growth factor I receptor is overexpressed in psoriatic epidermis, but is differentially regulated from the epidermal growth factor receptor.

Insulin-like growth factor I (IGF-I)/somatomedin C is an important mediator of keratinocyte growth in vitro, and the expression of IGF-I receptors in the basal layer of normal epidermis suggests that this growth pathway may function in the regulation of keratinocyte growth in vivo as well. The pattern of IGF-I receptor expression in normal skin is distinct from that of the epidermal growth factor (EGF) receptor, suggesting that these receptors might be differentially regulated. The purpose of this study was to obtain a better understanding of IGF-I receptor function in the skin by examining IGF-I receptor expression in psoriatic epidermis and in cultured human keratinocytes. Our findings indicate that IGF-I receptor expression is increased in psoriasis as measured by protein tyrosine kinase assays of biopsy extracts and by immunohistochemical staining with an IGF-I receptor-specific monoclonal antibody. Unlike EGF receptor expression, which is also increased in psoriatic epidermis, the pattern of IGF-I receptor expression corresponds closely with the increased size of the keratinocyte proliferative compartment in psoriasis. Biochemical agents that diminish EGF receptor ligand binding (phorbol ester or calcium ionophore treatment) produce opposite effects on the IGF-I receptor. These results suggest that cellular expression and differential regulation of both growth factor receptor systems may control critical aspects of epidermal proliferation or function.

Antibodies, Monoclonal↗
PubMed1992

Gastrointestinal manifestations of epidermolysis bullosa. A study of 101 patients.

One hundred one patients with EB were evaluated by a combination of prospective and retrospective review, and analyzed regarding the nature, incidence, and prevalence of their gastrointestinal (GI) manifestations. Involvement of the GI tract is a well-known extracutaneous manifestation of dystrophic EB, but it also occurred in more than one-half and one-third, respectively, of those with junctional and simplex EB. Most of the serious consequences, such as esophageal strictures and microstomia, occurred in recessive dystrophic EB but were also seen, although infrequently, in the junctional and simplex forms. The majority of patients with dysphagia had an esophageal stricture, and the cervical esophagus was the most common location. The onset of dysphagia generally occurred in the first decade of life, in patients much younger than previously recognized. Diagnostic endoscopy did not reveal lesions which could not have been detected radiographically. Lower GI complaints were common, especially constipation and perianal blistering, and affected all types of EB. These complaints contributed substantially to management problems but they did not correlate with colonic pathology and appeared to reflect anal or perianal disease.

Adolescent↗
PubMed1992

Studies of the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation.

Cyclosporine (CSA) decreases lymphokine synthesis and keratinocyte proliferation in vitro, but its in vivo mechanism of action in treating recalcitrant psoriasis is incompletely understood. Ten psoriasis patients were treated with CSA (2-7.5 mg/kg/d) with clinical improvement in nine of 10 patients. Skin biopsies before and after 1-3 months of CSA treatment were studied for evidence of immune and keratinocyte activation using immunoperoxidase and Northern blotting analysis. The number of activated, IL-2 receptor+ T cells in plaques after CSA treatment was reduced in all patients by a mean of 60%. Seven of 10 patients showed a decrease in keratinocyte HLA-DR expression; five of seven showed a decrease in gamma-IP-10 immunoreactivity, suggesting a decline in gamma interferon levels in plaques after CSA therapy. We studied the effect of CSA treatment in vivo on TGF-alpha, IL-6, and keratin K16 expression, three markers of keratinocyte growth activation. Expression of keratinocyte TGF-alpha and IL-6, which are elevated in active psoriatic epidermis, did not change in these patients after CSA treatment. The majority of patients (five of eight) continued to express the hyperproliferative keratin K16 after CSA treatment. Our results suggest that the predominant direct mechanism of action of Cyclosporine in vivo is a diminution of T-cell activation in plaques, with attendant decreased lymphokine production.

Cyclosporine↗
PubMed1992

Junctional epidermolysis bullosa of the larynx. Report of a case and literature review.

Epidermolysis bullosa (EB) is a group of rare inherited disorders in which minor trauma causes blister formation in the skin and mucosa, including the esophagus. Morbidity varies with the type of disease and ranges from occasional trivial skin blisters to death in infancy. Laryngeal involvement presenting as hoarseness and respiratory distress has been reported in nine patients, five of whom had junctional EB. We present the sixth case of junctional EB with laryngeal involvement, and offer guidelines for otolaryngologists and anesthesiologists caring for these fragile patients.

Child, Preschool↗
PubMed1991

Cyclosporine in psoriasis treatment. Inhibition of keratinocyte cell-cycle progression in G1 independent of effects on transforming growth factor alpha/epidermal growth factor receptor pathways.

Cyclosporine, an immunosuppressive drug, is effective in the treatment of recalcitrant psoriasis. Previous work suggested that keratinocyte hyperproliferation and inflammation are linked in psoriasis and that immune mechanisms participate in the pathogenesis of psoriasis. Transforming growth factor (TGF) alpha may be an important regulatory factor of epidermal growth as overproduction of TGF-alpha is associated with epidermal hyperplasia in psoriatic plaques and epidermal growth factor receptors are overexpressed in psoriatic epithelium. In this study, the effects of cyclosporine on cultured human keratinocytes were examined. Cyclosporine specifically inhibited keratinocyte cell-cycle progression in the G1 phase without causing keratinocytes to terminally differentiate. Cyclosporine did not decrease the expression of TGF-alpha or epidermal growth factor receptors. These results suggest that the effects of cyclosporine on psoriatic skin are unrelated to direct effects on autocrine growth regulation of keratinocytes via TGF-alpha production or of epidermal growth factor receptor modulation.

Chemokine CXCL10↗
PubMed1991

The ultrastructural defect in conjunctiva from a case of recessive dystrophic epidermolysis bullosa.

The predominant feature in the several forms of epidermolysis bullosa is the formation of cutaneous bullous lesions arising after minimal mechanical trauma. Ocular involvement has been noted as a complication. To our knowledge to date, only four investigators have correlated clinical eye disease with light microscopic findings. Ultrastructure of the ocular lesions has not been described previously. We present four cases of recessive dystrophic epidermolysis bullosa emphasizing their associated ocular complications. Diagnosis was confirmed by skin biopsy specimen and in one patient by demonstrating light and electron microscopic findings in eyelid skin. This tissue exhibited ultrastructural recessive cutaneous lesions; namely, bullous separation occurring below the basal lamina and absence of anchoring fibrils in both bullous and nonbullous areas. By electron microscopy, the conjunctiva in this patient exhibited an absence of clear anchoring fibrils that were numerous in control tissue. This defect may increase the susceptibility of the conjunctiva to minor mechanical trauma, resulting in the bullous and cicatricial changes seen clinically.

Aged↗
PubMed1991

Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry.

Inherited epidermolysis bullosa encompasses a number of diseases, with the common finding of blister formation after minor mechanical trauma to the skin. In some forms significant, if not eventually fatal, extracutaneous disease activity may occur. In recent years application of newer technologies has contributed substantially to an overall understanding of this collection of inherited diseases. Concurrently, many new phenotypes have been recognized, in part the result of ongoing prospective patient registries in the United States and abroad. Unfortunately, this has resulted in a massive literature that may appear to be confounded by seemingly excessive or arbitrary subdivision of epidermolysis bullosa variants. With these concerns in mind a subcommittee was established by the National Epidermolysis Bullosa Registry to summarize the current literature and to make recommendations as to the best clinical and laboratory criteria for the practical diagnosis and subclassification of patients with inherited epidermolysis bullosa.

Epidermolysis Bullosa↗
PubMed1991

Hypertriglyceridemia in patients with psoriasis treated with cyclosporine.

Eight patients received cyclosporine at doses of 2.0 to 7.5 mg/kg/day. Seven of these patients had increased fasting plasma triglyceride levels with cyclosporine therapy compared with pretreatment values, which peaked after 1 month of therapy. Four patients experienced elevations in fasting triglycerides, over the upper limits for age- and sex-matched controls, which were at least two times higher than their baseline values. It was striking that all four of these patients had previously had hypertriglyceridemia while using etretinate and three of these patients had preexisting hypertriglyceridemia before both etretinate and cyclosporine therapy. Triglyceride elevation did not correlate with cyclosporine levels. Thus cyclosporine, similar to etretinate, unmasks a latent tendency for mild to moderate hypertriglyceridemia. Fasting triglyceride levels should be monitored during cyclosporine therapy, especially after 1 to 2 months of use, and in patients with preexisting increased triglycerides and/or a history of etretinate use.

Adult↗
PubMed1991

Synergistic effects of epidermal growth factor (EGF) and insulin-like growth factor I/somatomedin C (IGF-I) on keratinocyte proliferation may be mediated by IGF-I transmodulation of the EGF receptor.

The epidermal growth factor (EGF) receptor pathway is an important mediator of keratinocyte growth in vitro and both receptor and ligand components of this pathway are abnormally expressed in hyperproliferative epidermis. The purpose of this study was to examine interactions between the EGF receptor pathway and the insulin-like growth factor I/somatomedin C (IGF-I) receptor pathway in modulating the growth of cultured normal human keratinocytes. Short-term growth of keratinocytes in a chemically defined medium demonstrated that neither EGF nor IGF-I alone could support significant keratinocyte spreading or proliferation, but that a combination of EGF with IGF-I or high-dose insulin could. IGF-I or high-dose insulin transmodulates keratinocyte EGF receptor expression via the IGF-I receptor in a dose- and time-dependent manner, increasing EGF receptor binding an average of 1.8 times up to a maximum of fourfold without altering EGF binding affinity. Staining of normal human epidermis with an IGF-I receptor specific monoclonal antibody demonstrates that IGF-I receptors localize to the basal proliferative cell compartment, suggesting that IGF-I receptor and EGF receptor pathway interactions may play a role in the regulation of epidermal growth and in the pathogenesis of hyperproliferative skin diseases.

Cell Division↗
PubMed1991

Effects of oxygen tension on the growth and pigmentation of normal human melanocytes.

The effects of oxygen tension on human melanocyte growth, tyrosinase activity, and melanin production were assessed. Melanocytes, seeded at 10(4) cells/cm2, were grown in modified Eagle's medium (MEM) with 5% fetal bovine serum (FBS) and 10 ng/ml 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Flasks were equilibrated with gas mixtures containing 5% CO2 and various partial pressures of oxygen (PO2 7-620 mm Hg) and kept in incubators, which were electronically maintained at the desired oxygen tensions. Melanocytes grew best at PO2 from 6-34 mm Hg. Growth was reduced by 30% at PO2 142 mm Hg, and even more at O2 tensions greater than 230 mm Hg. A PO2 of 603 mm Hg was cytotoxic. Tyrosinase activity (assayed by the method of Pomerantz) was 300 microU/mg protein at PO2 7-34 mm Hg. At PO2 235 and 355 mm Hg tyrosinase activity decreased to about 100 microU/mg protein. The apparent Km for tyrosine was unchanged in melanocytes cultured at all experimental oxygen tensions. The Vmax, however, was decreased at the higher oxygen tensions (PO2 235 mm Hg). At PO2 6-135 mm Hg the melanin content was proportional to tyrosinase activity. At cytostatic oxygen tensions (PO2 235 and 355 mm Hg) the intracellular melanin content increased somewhat, although tyrosinase activity was decreased. Low oxygen tension is favorable for both melanocyte proliferation and tyrosinase activity.

Cell Division↗
PubMed1991

Increased dermal expression of platelet-derived growth factor receptors in growth-activated skin wounds and psoriasis.

Platelet-derived growth factor (PDGF) is a potent mitogenic and chemotactic factor for fibroblasts and other cell types. PDGF effects are mediated by binding of PDGF to dimeric PDGF receptors possessing intrinsic tyrosine kinase activity. We examined the expression pattern of PDGF receptors in cryostat sections of normal and growth-activated human skin using a monoclonal antibody, PR7212, specific for the beta subunit of the PDGF receptor. PDGF receptors were expressed at low levels in normal skin, with only occasional staining of dermal connective tissue cells. In contrast, PDGF receptor expression was greatly elevated in the dermis of growth-activated skin from 15 chronic wounds and 10 psoriatic lesions. PDGF receptors were increased in dermal fibroblasts and in dermal blood vessels in both conditions. Immunoblot analysis confirmed the increased expression of beta-subtype PDGF receptors in psoriatic lesional tissue. PDGF receptors were not detected in normal or growth-activated epidermis. Differential expression of PDGF receptors could regulate increased proliferation of vascular and connective tissue cells observed in psoriasis and chronic wounds.

Antibodies, Monoclonal↗
PubMed1991

Junctional epidermolysis bullosa keratinocytes in culture display adhesive, structural, and functional abnormalities.

An unusual, elongated, refractile cell morphology was observed in keratinocytes cultured from three patients with non-lethalis forms of junctional epidermolysis bullosa (JEB). To determine whether these changes might be related to altered cell adhesion, keratinocyte strains established from one patient were examined for adhesive, structural, and functional characteristics. JEB keratinocytes expressed keratin tonofilaments, as determined by staining with AE1 monoclonal antibodies and direct observation of tonofilaments by electron microscopy. JEB keratinocytes showed diminished cell-substratum adhesions, judged by interference reflection microscopy. Areas of diminished cell-substratum adhesion corresponded to F-actin-rich cell adhesions (focal adhesions) and not to cellular areas that abundantly express hemidesmosomal antigens. Analysis of cell-substratum adhesion by electron microscopy revealed extensive areas of cell-substratum separation in JEB keratinocytes that were not present in normal keratinocytes maintained in serum-free medium. Normal keratinocytes displayed numerous regions of focal contact between the ventral plasma membrane and the culture substratum, but these structures were not seen in JEB keratinocytes. Bundled actin filaments (stress fibers) were greatly diminished in expected regions of cell-substratum adhesion in JEB keratinocytes and, instead, displayed disorganized individual filaments. The growth rate of JEB keratinocytes was quite slow in culture, with a population doubling time of 2.7 d versus 1.5 d for normal keratinocytes under identical conditions. JEB keratinocytes also displayed a reduced ability to aggregate into colonies upon exposure to medium with increased extracellular calcium. JEB keratinocytes thus display adhesive, structural, and functional abnormalities that suggest this cell type may be central to the pathogenesis of junctional epidermolysis bullosa. Study of affected keratinocytes could be important to characterize associated molecular pathologies.

Actins↗
PubMed1990

Mupirocin-resistant Staphylococcus aureus after long-term treatment of patients with epidermolysis bullosa.

In a long-term, open study, 47 patients with epidermolysis bullosa were treated with topical 2% mupirocin (Bactroban) ointment to decrease bacterial infection and promote wound healing. This antibiotic is effective against gram-positive but not gram-negative organisms. No significant adverse effects were noted, although some patients have been treated for more than 4 years. We sought evidence in this patient population for the appearance of bacterial strains with decreased sensitivity to mupirocin. In five patients cultures from nonhealing wounds revealed Staphylococcus aureus resistance to mupirocin. Four of these patients were given oral antibiotics to which S. aureus was sensitive; they improved clinically, and cultures of their wounds became negative for pathogens.

Adult↗
PubMed1990

Occlusive hydrocolloid dressings decrease keratinocyte population growth fraction and clinical scale and skin thickness in active psoriatic plaques.

Clinical studies suggest a therapeutic role for occlusion in the treatment of psoriasis. Previous studies, using multiparameter RNA/DNA flow cytometric analysis of epidermal suspensions obtained from active plaques, demonstrated increased keratinocyte growth fraction which reversed with successful medical treatment. Because keratinocyte growth fraction reflected disease activity, it was used in this study in addition to clinical evaluations in order to determine the efficacy of occlusion in the treatment of psoriatic plaques. In each of 9 patients, scale, skin thickness and erythema were compared in one occluded and one control plaque using an analog scale. Both scale and skin thickness, but not erythema, were decreased after 2 weeks of occlusion. However after 10 weeks, no additional differences were seen when compared with assessments made after 2 weeks, suggesting that the benefits of occlusive therapy occurred early. After 10 weeks of occlusion, the keratinocyte growth fraction was significantly decreased in occluded plaques. This study demonstrates that occlusion plays a synergistic role with other therapeutic modalities in ameliorating psoriatic plaques.

Bandages, Hydrocolloid↗
PubMed1990

Role of growth factors, cytokines, and their receptors in the pathogenesis of psoriasis.

Psoriasis is characterized by epidermal hyperplasia, altered epidermal maturation, and local accumulation of acute and chronic inflammatory cells. Keratinocyte hyperplasia in psoriasis may be explained in part by overproduction of growth factors or cytokines which stimulate epidermal proliferation and by altered metabolism of growth-factor receptors in affected skin. Psoriatic epidermis displays overproduction of TGF-alpha and interleukin-6 (IL-6), factors produced by keratinocytes and other cell types in psoriatic skin. TGF-alpha and IL-6 are mitogens for normal human keratinocytes and act via specific receptors. The TGF-alpha receptor (EGF receptor) is overexpressed in psoriatic epithelium and its altered expression could be caused in part by gamma interferon which prevents normal receptor down-regulation in response to EGF binding. Several phenotypic features of the psoriatic keratinocyte, including growth activation and expression of HLA-DR, gamma-IP-10, ICAM-1, and other molecules, are best explained as resulting from the combined effects of TGF-alpha, IL-6, and gamma interferon (and possibly other cytokines) on epidermal keratinocytes. The multiple histologic features of psoriasis, including epidermal hyperplasia and accumulation of acute and chronic inflammatory cells, may be mediated by defined growth factors and cytokines that are produced in psoriatic skin and affect the function of diverse cell types.

Animals↗