Biomedical subjects
Publications and source records attributed to S Burge.
Mycosis fungoides is a form of cutaneous lymphoma with a typically indolent course. We describe an unexpected, repeated response to a systemic antifungal agent, itraconazole. The mechanism of action is speculative but itraconazole has marked immunosuppressive activity on T-lymphocyte proliferation in vitro.
Chronic obstructive pulmonary disease (COPD) is defined independently of exacerbations, which are largely a feature of moderate-to-severe disease. This article is the result of a workshop that tried to define exacerbations of COPD for use in clinical, pharmacological and epidemiological studies. The conclusions represent the consensus of those present. This review describes definitions, ascertainment, severity assessments, duration and frequency, using varying sources of data including direct patient interview, healthcare databases and symptom diaries kept by patients in studies. The best general definition of a COPD exacerbation is the following: an exacerbation of COPD is a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations that is acute in onset and may warrant additional treatment in a patient with underlying COPD. A more specific definition for studies where a bacteriological cause of exacerbation is being studied is included, as well as simpler definitions for retrospective identification from database sources. Prospective diary card assessments are best recorded as changes from an agreed baseline, rather than absolute symptom severities. Diary cards identify many unreported exacerbations, which on average have similar severities to reported exacerbations. A scale for exacerbation severity is proposed that incorporates in- and outpatient assessments. Exacerbation duration, which also relates to severity, is defined from diary card reports. Healthcare utilisation is not an adequate substitute for severity, depending on many unrelated social and comorbidity factors. It is an outcome in its own right.
BACKGROUND: In 1993, the General Medical Council recommended that all medical schools should revise their curricula for undergraduate medical education and foster more interdisciplinary collaboration in teaching. In accordance with these recommendations, new curricula have been introduced in U.K. medical schools. OBJECTIVES: To assess the impact of changes in medical curricula on the teaching of dermatology to medical undergraduates. METHODS: A questionnaire was sent to the dermatologists responsible for organizing the teaching of undergraduate dermatology in each of the 24 medical schools in England, Scotland, Wales and Northern Ireland. RESULTS: Replies were received from all schools. Nineteen of the 24 schools had already introduced integrated curricula and the others were changing more slowly. Some dermatology was included in the core curriculum in all schools. Dermatologists in 14 schools contributed to the teaching of basic science and students in 18 schools were able in years 1 and 2 to see patients in primary care (14) and/or the hospital (13). In nine of these schools, students could meet dermatology patients in these early clinical sessions. Nine schools used some problem-based learning (PBL) in addition to other teaching methods, but PBL predominated in four schools and in two of these schools most students never met a dermatologist. Dermatology was a compulsory clinical attachment in 21 schools, but the length of attachments varied and was less than 5 days in four schools. Students had to pass a dermatology assessment at the end of the clinical attachment in 14 schools and there was assessment of knowledge of dermatology in final examinations in all schools. Students had an early opportunity to explore a dermatology topic in depth in 17 schools, and 20 schools offered or were planning to introduce special study modules in dermatology. Interdisciplinary teaching links were common. Resources for out-patient teaching were inadequate in 16 schools and university support poor in 10 schools. Few departments had direct access to the considerable health service funding that is paid to National Health Service Trusts to reimburse the costs of teaching medical students. CONCLUSIONS: In general, dermatology has maintained a reasonable profile in the new undergraduate curricula, but dermatology experience is inadequate in four schools. Dermatologists should maximize opportunities for introducing dermatology into the curriculum by familiarizing themselves with the forces that are driving curriculum reform, participating in curriculum development, keeping abreast of changes in medical education and using opportunities for interdisciplinary teaching.
BACKGROUND: The recent report that mutations in ATP2A2, which encodes the Ca2+ transporting sarco/endo-plasmic reticulum pump type 2 isoforms (SERCA2), cause Darier's disease (DD) suggests that SERCA2 plays an important role in epidermal cell adhesion and differentiation. However, no data exist regarding SERCA2 expression in normal human skin, mucosa and DD. OBJECTIVES: We have therefore investigated SERCA2 expression in normal human skin (40 samples), oral and vaginal mucosa (13 samples) and DD lesional skin (six samples). MATERIALS AND METHODS: These investigations were performed with a mouse monoclonal antibody specific for human SERCA2, using a standard ABC immunoperoxidase technique. RESULTS: SERCA2 was expressed in all specimens. SERCA2 expression was pronounced in the subnuclear aspect of basal epidermal keratinocytes, with variable suprabasal expression. SERCA2 expression was also observed in the infundibulum and outer root sheath of hair follicles; germinative and mature cells of sebaceous glands; secretory coil and duct of eccrine glands; apocrine gland cells, and arrector pili muscle. Fibroblasts and blood vessels (endothelium and muscle) expressed SERCA2, whereas nerves did not. SERCA2 expression was observed throughout oral and vaginal mucosa. In DD skin, strong SERCA2 positivity was detected in the basal, suprabasal and acantholytic lesional cells. Perilesional DD skin was comparable to normal skin. CONCLUSIONS: These findings support the hypothesis that SERCA2 is an important player in cutaneous biology, and provide baseline data that will facilitate the design and interpretation of functional studies of cutaneous SERCA2.
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A 6-year-old girl with consanguineous parents presented with a history of progressive ataxia and patchy, segmental pigmentary changes, some reminiscent of Blaschko's lines. There was no evidence of oculocutaneous telangiectases or signs of immunodeficiency. A clinical diagnosis of ataxia--telangiectasia (AT) was suggested and confirmed by the presence of a low serum IgA, raised alpha-fetoprotein and chromosomal rearrangements of chromosomes 7 and 14. This case of AT is unique for having hypopigmentation and hyperpigmented patches adjacent to each other, which is a feature that has been described as 'cutis tricolor', and is unusual for having pigmentary skin changes, some in the lines of Blaschko without telangiectases. Clinicians should be aware that a diagnosis of AT may be made in the absence of telangiectases.
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Chronic obstructive pulmonary disease (COPD) is a progressive disease with alveolar destruction (emphysema) and bronchiolar fibrosis (obstructive bronchitis) in variable proportions. Reducing disease progression, as assessed by forced expiratory volume in I second (FEV1) decline, health-related quality of life, exacerbation rate and mortality, is a more realistic outcome than physiological improvement. This paper reviews all the published studies of at least 100 patients followed for at least 2 years. Studies have included patients with mild COPD (Copenhagen City Lung Study) to advanced symptomatic disease [Inhaled Steroids in Obstructive Lung Disease (ISOLDE)], with 2 studies of those with relatively early symptoms [European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP) and Lung Health-21. Exacerbation frequency, and probably severity, are reduced by high dose inhaled corticosteroids. Exacerbations are only frequent in more advanced disease, limiting the use of this outcome in EUROSCOP and Lung Health-2. Exacerbations are associated with reduced health-related quality of life. ISOLDE clearly showed a reduced rate in decline of the disease-specific St George's Respiratory Questionnaire with fluticasone propionate, partly related to the reduced exacerbations. The symptom component of the score showed the greatest difference between placebo and fluticasone propionate. None of the larger studies were able to reproduce the statistically significant reduction in the rate of decline in FEV1 suggested by the smaller, earlier studies. This might at least in part be as a result of the statistical modelling used which cannot adequately compensate for those with more rapidly progressive disease dropping out earlier. The equivalent doses of inhaled corticosteroids differed approximately fivefold between the major studies. The more positive results were obtained with higher doses. Oropharyngeal adverse effects were similar to those seen in patients with asthma; bruising was increased in one study with budesonide, otherwise adverse effects were similar to placebo. Bone loss was specifically studied in subgroups of patients in EUROSCOP and Lung Health-2. Budesonide 800 microg/day was associated with less bone loss than placebo, whereas triamcinolone 1200 microg/day was associated with excess bone loss. High dose inhaled corticosteroids have a favourable risk/benefit ratio in patients with advanced disease, particularly those with frequent exacerbations, and no benefit for those with very mild disease. It is not possible from the data to make firm recommendations for the important intermediate group where delaying progression is likely to lead to greatest benefit. I believe high dose inhaled steroids are warranted for those with intermediate severity COPD, who have frequent exacerbations or significant COPD-related symptoms.
Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Previous genetic linkage studies localized the gene to a 5 cM interval on human chromosome 3q21. After reducing the disease critical region to <1 cM, we used a positional cloning strategy to identify the gene ATP2C1, which is mutated in HHD. ATP2C1 encodes a new class of P-type Ca(2+)-transport ATPase, which is the homologue for the rat SPLA and the yeast PMR1 medial Golgi Ca(2+)pumps and is related to the sarco(endo)plasmic calcium ATPase (SERCA) and plasma membrane calcium ATPase (PCMA) families of Ca(2+)pumps. The predicted protein has the same apparent transmembrane organization and contains all of the conserved domains present in other P-type ATPases. ATP2C1 produces two alternative splice variants of approximately 4.5 kb encoding predicted proteins of 903 and 923 amino acids. We identified 13 different mutations, including nonsense, frameshift insertion and deletions, splice-site mutations, and non-conservative missense mutations. This study demonstrates that defects in ATP2C1 cause HHD and together with the recent identification of ATP2A2 as the defective gene in Darier's disease, provide further evidence of the critical role of Ca(2+)signaling in maintaining epidermal integrity.
Epidermal naevi are localized malformations of the epidermis consisting of verrucoid scaly papules and plaques following Blaschko's lines. Genetic mosaicism has been proposed to underlie the development of linear epidermal naevi. Rarely, epidermal naevi show acantholytic histology similar to Darier's disease, a dominantly inherited skin condition characterized by widespread warty papules. As patients with acantholytic dyskeratotic naevi often give a history of worsening after sun exposure and the lesions are typical of Darier's disease, numerous authors have proposed that these patients have segmental Darier's disease. The postulated relationship has not been proven, however. Recently, we identified ATP2A2, which encodes the sarco/endoplasmic reticulum Ca(2+) ATPase isoform 2 as the defective gene in Darier's disease. In this report, we investigated the involvement of ATP2A2 in acantholytic dyskeratotic naevi following Blaschko's lines in two patients. We identified a nonsense mutation (Y894X) in the first patient and a nonconservative glycine to arginine mutation at codon 769 (G769R) in the other patient. These mutations were present in affected skin, and were not detected in unaffected skin or in leukocytes. We conclude that acantholytic dyskeratotic naevi can arise from a somatic mutation in ATP2A2. These individuals are mosaics for the mutation, but the risk of transmission of generalized Darier's disease will depend on whether the germline is affected. Our findings provide further evidence that Blaschko's lines do reflect genetic mosaicism and that the term acantholytic dyskeratotic naevus might be replaced in the future by segmental Darier's disease induced by postzygotic mosaicism. J Invest Dermatol 115:1144-1147 2000
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Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.
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Darier's disease is an uncommon inherited cutaneous disease which is difficult to manage, especially in adolescence. The warty keratotic papules irritate, smell and look unsightly. Histologically, the condition is characterized by the presence of focal acantholytic dyskeratosis. Treatment is unsatisfactory, particularly in patients with erosive flexural disease, but retinoids reduce the hyperkeratosis. Now the mutation causing Darier's disease has been identified, there is a real possibility of more effective treatment in the future.
We describe a 53-year-old man who developed partial and full thickness skin loss associated with pyrexia, diarrhoea, liver, renal and bone marrow failure, during treatment for an aggressive B cell lymphoblastic lymphoma. The clinical features and histology were compatible with both toxic epidermal necrolysis and graft vs. host disease, causing a diagnostic and therapeutic dilemma. We discuss the possibility that methotrexate was the causative drug, with review of its cutaneous side-effects. Histologically our patient demonstrated the sparse dermal infiltrate with full thickness epidermal necrosis typical of toxic epidermal necrolysis and graft vs. host disease. We discuss this finding with respect to the pathogenesis of toxic epidermal necrolysis.
Darier's disease (DD) is an autosomal dominantly inherited skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently, we identified ATP2A2 encoding the sarco/endoplasmic reticulum Ca(2+)ATPase isoform 2 as the defective gene in DD. Now we report a spectrum of ATP2A2 mutations in 19 families and six sporadic cases with DD and investigate genotype-phenotype correlations. All 21 exons and flanking intron boundaries were amplified and screened for mutations by conformation-sensitive gel electrophoresis and direct sequencing. We identified 24 novel mutations that are scattered throughout the ATP2A2 gene. Two families shared an identical mutation on a common disease-associated haplotype, suggesting inheritance from a common ancestor. The majority of the mutations (54%; 13/24) led to a premature termination codon which further supports the proposal that haploin-sufficiency is a common molecular mechanism for DD. Thirty-eight per cent of mutations (9/24) result in non-conservative amino acid substitutions at highly conserved positions. Two mutations predict mutated polypeptides lacking or carrying additional amino acids. Marked inter- and intrafamilial phenotypic variability of the disease was observed. These results illustrate the considerable diversity of ATP2A2 mutations causing DD and suggest that additional factors are important contributors to the clinical phenotype.
Darier's disease (DD) is a rare, dominantly inherited disorder that affects the skin producing a variety of types of lesion. Close examination of lesional DD skin shows the presence of abnormal keratinization (epidermal differentiation) and acantholysis (loss of cohesion) of keratinocytes. A number of clinical studies have described the co-occurrence of various neurological and psychiatric symptoms with DD, including mood disorders, epilepsy, mental retardation and a slowly progressive encephalopathy. A single locus for DD has been mapped to chromosome 12q23-q24.1, and a variety of missense, nonsense, frameshift and splicing mutations in the ATP2A2 gene have been described recently in families with DD. This gene encodes the sarcoplasmic/endoplasmic reticulum calcium-pumping ATPase SERCA2, which has a central role in intra-cellular calcium signalling. In this study, we performed mutation analysis on ATP2A2 in 19 unrelated DD patients, of whom 10 had neuropsychiatric phenotypes. We identified and verified 17 novel mutations predicting conservative and non-conservative amino acid changes, potential premature translation terminations and potential altered splicing. Our findings confirm that mutations in ATP2A2 are associated with DD. In neuropsychiatric cases, there was a non-random clustering of mutations in the 3' end of the gene ( P = 0.01), and a predominance of the missense type (70% versus 38% in DD patients). This supports the hypothesis that the DD gene has pleiotropic effects in brain and that mutations in SERCA2 are implicated in the pathogenesis of neuropsychiatric disorders.