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A M Farrell

Publications and source records attributed to A M Farrell.

At least 19 recordsLinked to original sources
PubMed2006

Cytokine alterations in lichen sclerosus: an immunohistochemical study.

BACKGROUND: Although the histology of lichen sclerosus is characteristic, the precise nature of the inflammatory changes and the signals provoking them is uncertain. OBJECTIVES: To delineate the inflammatory changes in lichen sclerosus more accurately by studying cytokine changes. METHODS: An immunohistochemical study of 12 specimens of genital lichen sclerosus and one specimen of extragenital lichen sclerosus was undertaken using monoclonal antibodies to interferon (IFN)-gamma, IFN-gamma receptor, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-2 receptor (CD25), intercellular adhesion molecule-1 (ICAM-1) and its ligand CD11a. Control specimens were seven specimens of normal vulva obtained during gynaecological procedures, three specimens of normal skin, adjacent uninvolved thigh from three of the patients with lichen sclerosus, five specimens of nonvulval psoriasis, four specimens of nonvulval lichen planus and two specimens from chronic wounds. RESULTS: The lichen sclerosus specimens demonstrated slightly increased staining for IFN-gamma within the epidermis compared with the normal vulva and nonvulval skin. There was increased dermal staining for IFN-gamma both within the pale zone of the upper dermis and within the inflammatory zone below this. We confirmed our previous demonstration that in lichen sclerosus HLA-DR immunostaining is increased in association with vascular endothelium, the inflammatory cell infiltrate and around the keratinocytes. The areas of the epidermis with the strongest immunostaining for HLA-DR generally also had the strongest staining for IFN-gamma. In the lichen sclerosus specimens the zone of inflammation also demonstrated increased immunostaining for TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 while the zone of sclerosus demonstrated a smaller increase in immunostaining for IFN-gamma receptor, TNF-alpha, CD11a and ICAM-1, and the epidermis demonstrated increased staining for ICAM-1. CONCLUSIONS: The increased staining for IFN-gamma, TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 suggest that the cytokine response in lichen sclerosus shares characteristics of the cytokine response in lichen planus and chronic wounds.

Aged↗
PubMed2006

Childhood cicatricial pemphigoid confined to the vulva.

Cicatricial pemphigoid or benign mucous membrane pemphigoid is an autoimmune bullous disease predominantly affecting the mucosal surfaces and healing with scar formation. Localized cicatricial pemphigoid of the vulva in children is rare. We present a child with this rare condition who was initially investigated on suspicion of her being subjected to child sexual abuse, and discuss its management.

Administration, Topical↗
PubMed2004

Intestinal bypass syndrome presenting as erythema nodosum.

Intestinal bypass was a popular surgical procedure for morbid obesity resulting, on average, in a 50 kg weight loss. We describe a 66-year-old woman who underwent the procedure 12 years earlier and subsequently presented with recurrent episodes of erythema nodosum-like lesions. Further investigations revealed hyperoxaluria, renal failure, deficiency of fat-soluble vitamins (causing night blindness, osteomalacia and easy bruising) and anaemia. Antibiotics led to only temporary remission and, as with 24-30% of similar cases, she underwent surgical reversal to prevent the complications from worsening.

Aged↗
PubMed2002

Kytococcus sedentarius, the organism associated with pitted keratolysis, produces two keratin-degrading enzymes.

AIMS: To determine characteristics of the extracellular enzyme activity of Kytococcus sedentarius on human callus. METHODS AND RESULTS: A concentrate of a continuous culture supernatant fluid of K. sedentarius, which had callus-degrading activity, was subjected to a series of chromatographic purification procedures. The enzyme activity was found to be attributable to two proteases. These were capable of degrading both native callus and extracted keratin polypeptides and were purified to homogeneity, as shown by SDS-PAGE with silver staining. The enzymes P1 and P2 were 30 kDa and 50 kDa in size with isoelectric points of 4.6 and 2.7, respectively. The optimum conditions for callus-degrading activity were 40 degrees C, pH 7.1 for P1 and 50 degrees C, pH 7.5 for P2. P2 displayed increased activity in the presence of 800 mmol l(-1) NaCl and both enzymes were inhibited by PMSF (1 mmol(-1) Phenylmethylsulphoryl fluoride) and 1 mmol l(-1) EDTA. The main enzyme cleavage sites were Lys-Trp, Val-Lys, Gly-Asp and Asp-Arg, as determined after incubation of P1 and P2 with the beta-chain of insulin. CONCLUSIONS: K. sedentarius produces two extracellular enzymes that independently degrade natural, insoluble human callus. Both enzymes are serine proteases and have cleavage preference sites that are present in a range of human keratins. SIGNIFICANCE AND IMPACT OF THE STUDY: The identification, in K. sedentarius cultures, of two enzymes which can degrade human callus strengthens the hypothesis that this organism is responsible for the pitting in human epidermis observed in pitted keratolysis. These enzymes may be of commercial use in the biodegradation of a range of keratin polymers, biological washing powders and in the treatment of unwanted callus on human skin.

Actinomycetales↗
PubMed2001

A rapid flow cytometric assay to detect CD4+ and CD8+ T-helper (Th) 0, Th1 and Th2 cells in whole blood and its application to study cytokine levels in atopic dermatitis before and after cyclosporin therapy.

BACKGROUND: The immune response in atopic dermatitis (AD) is thought to be driven by T-helper (Th) 2 cytokines. Using flow cytometry, higher frequencies of peripheral blood CD4+ and CD8+ T cells producing interleukin (IL)-4 and correspondingly lower frequencies of CD4+ T cells producing interferon (IFN)-gamma have been found in patients with AD compared with healthy controls. It would be of interest to know whether other Th1 and Th2 cytokines such as IL-5, IL-13 and tumour necrosis factor (TNF)-alpha are similarly skewed in patients with AD and whether this immune skewing, detected via a simple blood assay, can be correlated with other clinical measurements or treatments in AD. OBJECTIVES: To use a rapid (4-h) flow cytometric assay to study a wide range of Th1 and Th2 cytokine patterns in peripheral blood lymphocytes from patients with AD, comparing them with non-atopic healthy controls. To correlate cytokine patterns with the degree of eosinophilia observed and in the case of one patient with severe disease, to observe the effect of cyclosporin therapy on peripheral blood cytokine patterns. METHODS: Peripheral blood from eight patients with AD and 23 healthy controls was examined for the frequencies of CD4+ and CD8+ T cells expressing IL-2, IL-4, IL-5, IL-13, IFN-gamma and TNF-alpha using flow cytometry. RESULTS: Significantly higher frequencies of CD4+/IL-4+ (P < 0.005) and CD4+/IL-13+ (P < 0.0001) and lower frequencies of CD4+/IFN-gamma+ (P < 0.002) and CD8+/TNF-alpha+ (P < 0.05) T lymphocytes were found in patients with AD compared with controls. There were significant positive correlations with the increased percentages of CD4+/IL-4+ and CD4+/IL-13+ T lymphocytes and the degree of eosinophilia observed (P < 0.05, P < 0.001) and a negative correlation between the percentage of CD4+/IFN-gamma+ T lymphocytes and eosinophilia (P < 0.05). In one patient examined before and 8 days after cyclosporin therapy, 50% or greater reductions were observed in percentages of peripheral blood CD8+/IL-5+, CD8+/IL-13+, CD4+/IL-4+ and CD4+/IL-5+ T lymphocytes following cyclosporin therapy. A smaller reduction of 15% after cyclosporin therapy was found in percentages of CD4+/IL-13+ T cells. CONCLUSIONS: These data strongly support a Th2 predominance in the peripheral blood of AD. The results suggest that administration of cyclosporin therapy in patients with AD may help to restore the Th2 cytokine imbalance seen in these patients.

Adult↗
PubMed2001

Alterations in fibrillin as well as collagens I and III and elastin occur in vulval lichen sclerosus.

BACKGROUND: The clinical features of lichen sclerosus, which include atrophy, scarring, fragility and tendency to form ecchymoses with only slight trauma, suggest that there is an alteration in the extracellular matrix fibres that are responsible for the tensile strength of the dermis. However, the precise nature of these changes is poorly understood. METHODS: Biopsies from 16 patients with untreated, histologically confirmed, vulval lichen sclerosus were examined immunohistochemically using polyclonal antibodies to collagens I and III and a monoclonal antibody to elastin. Twelve of the lichen sclerosus specimens were also stained with a monoclonal antibody to fibrillin. Normal vulva tissue and patients' uninvolved thigh were used as controls. RESULTS: In the lichen sclerosus specimens, collagens I and III stained with a more homogeneous pattern than in the control tissues. Reduced numbers of elastin fibres were seen in the zone of sclerosus in 15 of the 16 lichen sclerosus specimens. In the control tissue fibrillin fibres were seen as a fine network of fibres in the upper dermis arranged at right angles to and inserting into the basement membrane and forming a fine network throughout the dermis. In the lichen sclerosus specimens, although fibrillin microfibrils were still seen inserting at right angles into the basement membrane, below this the fibrillin staining was reduced in the upper dermis in 11 of the 12 lichen sclerosus specimens. The zone of reduced fibrillin staining was greatest in those specimens where the band of inflammation was deep in the dermis. CONCLUSIONS: The distribution of collagens I and III, elastin and fibrillin are altered in lichen sclerosus and this is likely to contribute to the fragility, scarring and atrophy seen clinically in lichen sclerosus.

Collagen Type I↗
PubMed2001

Distribution of transforming growth factor-beta isoforms TGF-beta 1, TGF-beta 2 and TGF-beta 3 and vascular endothelial growth factor in vulvar lichen sclerosus.

OBJECTIVE: To study the distribution of transforming growth factor beta (TGF-beta) isoforms TGF-beta 1, TGF-beta 2 and TGF-beta 3 and vascular endothelial growth factor (VEGF) in vulvar lichen sclerosus. STUDY DESIGN: Biopsies were obtained from 10 patients with vulvar lichen sclerosus, snap frozen and stained with polyclonal antibodies to TGF-beta 1, TGF-beta 2, TGF-beta 3 and VEGF. Control tissues used were uninvolved thigh tissue from two of the lichen sclerosus patients and normal vulvar tissue obtained from eight patients during gynecologic procedures. Two specimens of morphea were also examined. RESULTS: Weak TGF-beta 1 staining was demonstrated in the epidermis of all the lichen sclerosus, morphea, thigh and five of the eight normal vulvar specimens. Slight increase in TGF-beta 1 staining was seen in the upper and middermis in 6 of the 10 lichen sclerosus specimens and in the morphea specimens as compared to the control tissue, and this staining was localized within cells. TGF-beta 2 staining was present throughout the epidermis in all the normal thigh, normal vulva, lichen sclerosus and morphea specimens. TGF-beta 2 staining was increased within cells in the upper and middermis of the lichen sclerosus and morphea specimens. TGF-beta 3 staining occurred in the basal half of the epidermis of all the control, lichen sclerosus and morphea specimens, and only slight upper dermal staining of a few individual cells was seen in 3 of the 10 lichen sclerosus specimens. VEGF staining was similar in the normal tissues, lichen sclerosus and morphea. CONCLUSION: These results suggest that TGF-beta may.

Biopsy↗
PubMed2000

Generating a high affinity scorpion toxin receptor in KcsA-Kv1.3 chimeric potassium channels.

The crystal structure of the bacterial K(+) channel, KcsA (Doyle, D. A., Morais, C. J., Pfuetzner, R. A., Kuo, A., Gulbis, J. M., Cohen, S. L., Chait, B. T., and MacKinnon, R. (1998) Science 280, 69-77), and subsequent mutagenesis have revealed a high structural conservation from bacteria to human (MacKinnon, R., Cohen, S. L., Kuo, A., Lee, A., and Chait, B. T. (1998) Science 280, 106-109). We have explored this conservation by swapping subregions of the M1-M2 linker of KcsA with those of the S5-S6 linker of the human Kv-channel Kv1.3. The chimeric K(+) channel constructs were expressed in Escherichia coli, and their multimeric state was analyzed after purification. We used two scorpion toxins, kaliotoxin and hongotoxin 1, which bind specifically to Kv1.3, to analyze the pharmacological properties of the KcsA-Kv1.3 chimeras. The results demonstrate that the high affinity scorpion toxin receptor of Kv1.3 could be transferred to KcsA. Our biochemical studies with purified KcsA-Kv1.3 chimeras provide direct chemical evidence that a tetrameric channel structure is necessary for forming a functional scorpion toxin receptor. We have obtained KcsA-Kv1.3 chimeras with kaliotoxin affinities (IC(50) values of approximately 4 pm) like native Kv1.3 channels. Furthermore, we show that a subregion of the S5-S6 linker may be an important determinant of the pharmacological profile of K(+) channels. Using available structural information on KcsA and kaliotoxin, we have developed a structural model for the complex between KcsA-Kv1.3 chimeras and kaliotoxin to aid future pharmacological studies of K(+) channels.

Amino Acid Sequence↗
PubMed2000

Do plasminogen activators play a role in lichen sclerosus?

The histological changes of lichen sclerosus suggest that significant remodelling of the extracellular matrix is occurring. As the proteases of the plasminogen activator system have been implicated in tissue remodelling, cell migration and tumour invasion, we performed an immunohistochemical study to look for evidence of alteration in the expression of plasminogen/plasmin, urokinase-type plasminogen activator, tissue-type plasminogen activator and alpha2-antiplasmin in biopsies of clinically typical vulval lichen sclerosus obtained from 11 untreated adult women. Normal vulva obtained from gynaecological procedures and samples of the patients' uninvolved thigh tissue were used as controls. No significant difference was seen in the staining pattern between the lichen sclerosus tissue and control tissue. However, although we found no immunohistochemical evidence that the plasminogen activator system is involved in the pathogenesis of vulval lichen sclerosus, it may be that other proteases are involved.

Adult↗
PubMed2000

Regulation of HMG-CoA synthase and HMG-CoA reductase by insulin and epidermal growth factor in HaCaT keratinocytes.

Synthesis of cholesterol, via the isoprenoid/mevalonate pathway, is required for keratinocyte growth and differentiation, and maintenance of the stratum corneum lipid lamellae. 3-hydroxy-3-methylglutaryl coenzyme A synthase catalyzes the first step in isoprenoid/mevalonate synthesis and under some conditions controls the flux into the pathway. We have investigated whether selected growth factors and hormones could increase 3-hydroxy-3-methylglutaryl coenzyme A synthase mRNA in keratinocytes. Northern blotting was used to demonstrate that 10 microg per ml insulin and 0.1 microg per ml epidermal growth factor both increased steady-state levels of 3-hydroxy-3-methylglutaryl coenzyme A synthase mRNA by 2.5 and 6-fold, respectively. Epidermal growth factor and insulin also increased 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme activity. 3-hydroxy-3-methylglutaryl coenzyme A synthase promoter activity in a luciferase reporter construct was increased 2-fold by insulin and 2.9-fold by epidermal growth factor. When a mutation in the sterol regulatory element was introduced into the 3-hydroxy-3-methylglutaryl coenzyme A synthase promoter, activity was not increased by insulin, but was increased by epidermal growth factor. Mutation of an AP-1 site in the 3-hydroxy-3-methylglutaryl coenzyme A synthase promoter did not affect the increase in activity following treatment with insulin or epidermal growth factor. Therefore, 3-hydroxy-3-methylglutaryl coenzyme A synthase expression in keratinocytes is regulated by insulin and epidermal growth factor by different mechanisms. These results suggest a role for hormones and growth factors in the control of epidermal cholesterol synthesis.

Binding Sites↗
PubMed2000

Genital lichen sclerosus associated with morphoea or systemic sclerosis: clinical and HLA characteristics.

Although patients with both morphoea and lichen sclerosus have been reported previously, in the majority of these reports the lichen sclerosus has been extragenital. We report nine patients in whom genital lichen sclerosus coexisted with scleroderma spectrum disorders including seven with morphoea, one with morphoea and lichen planus, and one with systemic sclerosis. The clinical features, associated autoimmune disease, autoantibodies and HLA type are reported. Antibodies to Borrelia burgdorferi were not detected in any of the patients. The coexistence of these diseases raises a number of intriguing questions about the relationship between them.

Aged↗
PubMed2000

Alterations in distribution of tenascin, fibronectin and fibrinogen in vulval lichen sclerosus.

BACKGROUND: The pathophysiology of lichen sclerosus remains uncertain. The clinical features, including increased fragility and scarring, and the histology suggest that significant reorganisation of the extracellular matrix is occurring. Tenascin, fibrinogen and fibronectin are extracellular matrix components that play a significant role in tissue remodelling, for example during wound repair. AIM: To examine the distribution of tenascin, fibrinogen and fibronectin in vulval lichen sclerosus. MATERIALS AND METHODS: Immunohistochemical staining was performed to study the distribution of tenascin, fibronectin and fibrinogen in 16 specimens of untreated vulval lichen sclerosus and 1 specimen of extragenital lichen sclerosus. Haematoxylin and eosin staining of the specimens was also performed to identify the position of the pale staining homogenous zone/zone of sclerosis and the inflammatory infiltrate below this. The control tissues studied included biopsies taken from the uninvolved thigh of 13 of the lichen sclerosus patients and 6 samples of normal vulva tissue obtained during gynaecological procedures from women of similar age to the lichen sclerosus women. RESULTS: All the lichen sclerosus specimens demonstrated increased immunostaining of tenascin in the upper dermis and comparing this with the haematoxylin and eosin staining this corresponded to the zone of sclerosis with relatively little tenascin staining associated with the inflammatory band. In 14 out of the 16 vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen fibrinogen immunostaining was increased in the upper dermis which corresponded--in haematoxylin and eosin staining --to the zone of sclerosis. There was also slightly increased fibrinogen staining in the mid dermis which corresponded to the inflammatory band. Fibronectin staining was reduced in the upper dermis of 12 of the vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen which corresponded to the zone of sclerosis. However, in 14 of the vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen, fibronectin was slightly increased in the mid and deeper dermis which corresponded to the zone of inflammatory cells and the area below this. There was also increased fibronectin staining around blood vessel walls both in the mid dermis and within the zone of sclerosis. CONCLUSION: The distribution of tenascin, fibrinogen and fibronectin is altered in lichen sclerosus and the alteration in these extracellular matrix components may be relevant to the initiation of scarring in lichen sclerosus and the associated increased skin fragility.

Extracellular Matrix Proteins↗
PubMed1999

Cutaneous granulomas associated with high-grade T-cell non-Hodgkin's lymphoma.

We describe a patient with non-Hodgkin's lymphoma treated with a chemotherapy regimen (which included bleomycin, prednisolone and low-dose methotrexate) who developed cutaneous non-caseating granulomas. We felt our patient fitted into the category of 'sarcoid-like granulomas'.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Childhood vulval pemphigoid: a clinical and immunopathological study of five patients.

We describe five girls with vulval pemphigoid: two had bullous pemphigoid confined to the vulva and three had cicatricial pemphigoid. They demonstrate a spectrum of severity from localized disease to extensive vulval scarring necessitating long-term immunosuppressive therapy and surgical correction. The age at onset of their disease ranged between 6 and 13 years. All presented with vulval discomfort and erosions. Three had oral lesions, two perianal and one eye and cutaneous involvement. Two girls with only vulval lesions and one with vulval and oral lesions responded well to topical steroids. In two, systemic treatment with prednisolone and dapsone or azathioprine was required. The diagnosis was made on the basis of histology and immunofluorescence (IF). All had positive direct IF with IgG and C3. Indirect IF demonstrated circulating IgG binding to the basement membrane zone in four, with dermal or epidermal binding on salt-split skin substrate. Immunoblotting revealed antibodies to the BP230 and BP180 antigens. Immunoelectron microscopy in the child with dermal binding IgG and BP180 and BP230 on immunoblotting showed labelling at the lamina densa-lamina lucida interface adjacent to hemidesmosomes.

Adolescent↗
PubMed1999

Paget's disease of the vulva associated with local adenocarcinoma and previous breast adenocarcinoma: report of two cases.

We report two women in whom vulval Paget's disease occurred in association with local adenocarcinoma and previous breast adenocarcinoma. The first patient presented at the age of 83 years with moist erythematous changes over the perineum and an indurated area near the anus. Biopsy of the indurated area showed Paget's cells throughout the epidermis and, below, adenocarcinoma infiltrating the dermis. Ten years previously, she had undergone a left mastectomy for infiltrating ductal carcinoma of the breast. The second patient was diagnosed as having Paget's disease at the age of 74 years. A vulval biopsy showed Paget's cells in the epidermis but, in addition, there were changes suggestive of adenocarcinoma of the sweat glands. Her symptoms of vulval itching had started at the age of 45 years and had led to a simple vulvectomy at the age of 57 years. Retrospective review of this vulvectomy specimen showed Paget's disease. She had also previously been treated for infiltrating ductal adenocarcinoma of the breast and adenocarcinoma of the rectum. The management of Paget's disease is difficult because of its high recurrence rate and, as illustrated by our two cases, treatment is difficult if the patients are elderly and in poor general health.

Adenocarcinoma↗
PubMed1999

Benign familial Degos disease worsening during immunosuppression.

We describe a 61-year-old woman with skin lesions consistent with those found in Degos disease, both in clinical and in histological appearance. She had had several of these lesions for many years, as had her mother, sister and niece. In 1991, she underwent cadaveric renal transplantation and was treated with immunosuppression: prednisolone, azathioprine and cyclosporin. At that time, she developed many more characteristic skin lesions, and these were slightly larger and more noticeable than those she had had previously. She and the other affected family members appear to fit into the more benign subgroup of Degos disease, and it seems that her immunosuppression aggravated her cutaneous disease.

Female↗