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Biomedical subjects

A M Farrell

Publications and source records attributed to A M Farrell.

At least 19 recordsLinked to original sources
PubMed1998

Pyoderma gangrenosum of the penis.

Two cases of pyoderma gangrenosum involving the penis are presented. Treatment was difficult in both cases despite the use of high doses of prednisolone. In one case, the addition of thalidomide proved successful, whereas in the other, minocycline effected a cure.

Adult↗
PubMed1998

Benign cutaneous Degos' disease.

We report the case of a 44-year-old woman with Degos' disease who also had a lupus anticoagulant. Electron microscopy of the mature lesions showed interwoven tubular structures within the endothelial cells, as have been observed in previous cases of Degos' disease. Four years after her first cutaneous lesions, there is no evidence of involvement of other organs. Aspirin (300 mg daily) has arrested the cutaneous disease.

Adult↗
PubMed1998

Expression and regulation of mRNA for putative fatty acid transport related proteins and fatty acyl CoA synthase in murine epidermis and cultured human keratinocytes.

The epidermis has a requirement for fatty acids in order to synthesize cellular membranes and the extracellular lipid lamellar membranes in the stratum corneum. Despite high endogenous production of fatty acids the transport of exogenous essential fatty acids into the epidermis is an absolute requirement. Fatty acid uptake by keratinocytes has been shown to be mediated by a transport system. In this study we determined in murine epidermis and human cultured keratinocytes the expression of three putative fatty acid transport related proteins and fatty acyl CoA synthase, an enzyme that facilitates the uptake of fatty acids by promoting their metabolism. In cultured human keratinocytes, mRNA for fatty acid transport protein (FATP), plasma membrane fatty acid binding protein (FABP-pm), and fatty acyl CoA synthase (FACS) were detectable. Differentiation, induced by high calcium, did not affect FATP mRNA levels, but resulted in an approximately 50% increase in FACS mRNA, while decreasing FABP-pm mRNA by 50%. Fatty acid translocase (FAT) mRNA was not detected in cultured human keratinocytes. In murine epidermis, FATP, FABP-pm, FACS, and FAT mRNA were all present. Barrier disruption by either tape stripping or acetone treatment increased FAT mRNA levels by approximately 2-fold without affecting FATP, FABP-pm, or FACS. Occlusion with an impermeable membrane immediately after barrier disruption completely blocked the increase in FAT mRNA levels, indicating that this increase is related to barrier disruption rather than a nonspecific injury effect. In summary, this study demonstrates that several putative fatty acid transport related proteins as well as fatty acyl CoA synthase are expressed in keratinocytes and epidermis, and that the expression of these proteins may be regulated by differentiation and/ or barrier disruption.

Animals↗
PubMed1998

Parallel regulation of sterol regulatory element binding protein-2 and the enzymes of cholesterol and fatty acid synthesis but not ceramide synthesis in cultured human keratinocytes and murine epidermis.

After permeability barrier perturbation there is an increase in the mRNA levels for key enzymes necessary for lipid synthesis in the epidermis. The mechanism(s) responsible for this regulation is unknown. Sterol regulatory element binding proteins-1a, 1c, and -2 (SREBPs) control the transcription of enzymes required for cholesterol and fatty acid t synthesis in response to modulations of sterol levels. We now demonstrate that SREBP-2 is the predominant SREBP in human keratinocytes and murine epidermis, while SREBP-1 is not detected. Sterols regulate SREBP-2 mRNA levels in keratinocytes and the epidermis and the proteolytic cleavage of SREBP-2 to the mature active form in keratinocytes. In parallel to the increase in mature active SREBP, there is a coordinate increase in mRNA levels for cholesterol (HMG-CoA reductase, HMG-CoA synthase, farnesyl diphosphate synthase, and squalene synthase) and fatty acid (acetyl-CoA carboxylase, fatty acid synthase) synthetic enzymes. However, mRNA levels for serine palmitoyl transferase (SPT), the first committed step for ceramide synthesis, do not increase in parallel. The increase of mRNA for enzymes required for epidermal cholesterol and fatty acid synthesis is consistent with both the previously described early increase of cholesterol and fatty acid synthesis after barrier disruption and a role for SREBP-2 in the regulation of cholesterol and fatty acid synthesis for epidermal barrier homeostasis. In contrast, SPT appears to be regulated by different mechanisms, consistent with the different time course of its stimulation after barrier disruption.

Acetyl-CoA Carboxylase↗
PubMed1998

Acquired ichthyosis, alopecia and loss of hair pigment associated with leiomyosarcoma.

Acquired ichthyosis is an important clinical finding; internal malignancy, systemic disease and medication are recognised associations. We present a 70-year-old lady with acquired ichthyosis and leiomyosarcoma, one of the less frequently associated malignancies. An additional unusual finding was generalised thinning and loss of pigment affecting her hair. Scalp biopsy showed histological evidence of ichthyosis. Following resection of the tumour the ichthyosis resolved and there was regrowth of darker hair.

Aged↗
PubMed1998

UVB irradiation up-regulates serine palmitoyltransferase in cultured human keratinocytes.

The enzyme serine palmitoyltransferase (SPT; EC 2.3.1.50), which catalyzes the first committed and rate-limiting step in sphingolipid synthesis, is up-regulated in the epidermis as part of the homeostatic repair in response to permeability barrier perturbation. Moreover, UVB exposure, which also perturbs the barrier, up-regulates sphingolipid synthesis, but the basis for this increase is not known. The recent isolation of cDNAs for SPT (i.e., LCB1 and LCB2) allow molecular regulation studies to be performed. Therefore, we determined whether UVB exposure alters mRNA, protein, or activity levels for SPT in cultured human keratinocytes (CHKs) as a mechanism for regulation of epidermal sphingolipid synthesis. In CHK, transcripts for both LCB1 (3.0 kb) and LCB2 (2.3 kb) are evident by Northern blot analysis, and UVB exposure (23 mJ/cm2) induces a delayed 1.8 to 3.3-fold increase in LCB2 mRNA levels (P < 0.01) 48 h after treatment versus non-irradiated control cells. In contrast, neither LCB1 nor a second LCB2 transcript (8.0 kb) changed significantly. Likewise, Lcb2 protein levels (by Western blot analysis), as well as SPT activity, increase in parallel with the increased LCB2 mRNA. Finally, incorporation of [14C]-acetate into sphingolipids was increased significantly 48 h after UVB treatment. Together, these results demonstrate that CHKs respond to UVB by increasing sphingolipid synthesis, primarily through increases in both LCB2 mRNA and protein levels, leading to increased SPT activity. These results demonstrate one mechanism (UVB) whereby SPT is regulated at the molecular level, and suggest further that epidermis up-regulates sphingolipid synthesis at both the mRNA and protein levels in response to UVB.

Acetates↗
PubMed1997

Permeability barrier disruption coordinately regulates mRNA levels for key enzymes of cholesterol, fatty acid, and ceramide synthesis in the epidermis.

The extracellular lipids of the stratum corneum, which are comprised mainly of cholesterol, fatty acids, and ceramides, are essential for epidermal permeability barrier function. Moreover, disruption of the permeability barrier results in an increased cholesterol, fatty acid, and ceramide synthesis in the underlying epidermis. This increase in lipid synthesis has been shown previously to be due to increased activities of HMG-CoA reductase, acetyl-CoA carboxylase, fatty acid synthase and serine palmitoyl transferase, key enzymes of cholesterol, fatty acid, and ceramide synthesis, respectively. In the present study, we determined whether the mRNA levels for the key enzymes required for synthesis of these three classes of lipids increase coordinately during barrier recovery. By northern blotting, the steady-state mRNA levels for HMG-CoA reductase, HMG-CoA synthase, farnesyl pyrophosphate synthase, and squalene synthase, key enzymes for cholesterol synthesis, all increased significantly after barrier disruption by either acetone or tape stripping. Additionally, the steady-state mRNA levels of acetyl-CoA carboxylase and fatty acid synthase, required for fatty acid synthesis, as well as serine palmitoyl transferase, the rate-limiting enzyme of de novo ceramide synthesis, also increased. Furthermore, artificial restoration of the permeability barrier by occlusion after barrier disruption prevented the increase in mRNA levels for all of these enzymes, except farnesyl pyrophosphate synthase, indicating a specific link of the increase in mRNA levels to barrier requirements. The parallel increase in epidermal mRNA levels for the enzymes required for cholesterol, fatty acid, and ceramide synthesis may be due to one or more transcription factors that regulate lipid requirements for permeability barrier function in keratinocytes.

Acyltransferases↗
PubMed1997

Constitutive endothelial and inducible nitric oxide synthase in inflammatory dermatoses.

We have used immunohistochemistry to localize the expression of the constitutive endothelial and inducible forms of the enzyme nitric oxide synthase (NOS) in skin from involved and uninvolved sites in patients with atopic dermatitis (AD) and allergic contact dermatitis (CD). Endothelial NOS (eNOS) immunoreactivity was localized to vascular endothelium in the dermis of both involved and uninvolved skin from all patients. Inducible NOS (iNOS) immunoreactivity was found to be closely associated with the upper dermal microvasculature in all the involved AD biopsies, but only in two of 10 uninvolved AD biopsies. CD biopsies were taken from 10 positive skin patch test sites and iNOS immunoreactivity was detected in all of these. iNOS immunoreactivity was detected in only one of the negative patch test biopsies. Both the extent and intensity of iNOS immunoreactivity was lower in CD than in AD skin lesions. The presence of eNOS in the skin is necessary for constitutive NO-mediated dilatation of the dermal vasculature. Induction of iNOS in the dermal endothelium and in perivascular inflammatory cells may be significant with respect to the roles of NO in both the vasodilatory component of the inflammatory response and in the modulation of immune responses in the skin.

Dermatitis, Allergic Contact↗
PubMed1996

Staphylococcal scalded skin syndrome in an HIV-1 seropositive man.

The staphylococcal scalded skin syndrome (SSSS) is very rare in adults. Renal impairment and immunocompromise are predisposing causes. We report a 38-year-old HIV-1 seropositive intravenous drug abuser who developed SSSS due to staphylococcal pneumonia. An exfoliating toxin-releasing Staphylococcus aureus, phage type II type 3C, was isolated from the sputum and from blood cultures. This is the third case of adult SSSS to be reported in the context of HIV disease.

AIDS-Related Opportunistic Infections↗
PubMed1996

Scleredema diabeticorum of Buschke confined to the thighs.

We describe a patient with insulin-dependent diabetes without vascular complications in whom scleredema was confined to the thighs. Electron microscopy demonstrated heterogeneity in both the size and density of the collagen fibrils and the presence of filamentous material between them.

Adult↗