Clinical outcomes and response to treatment of patients receiving topical treatments for pyoderma gangrenosum: a prospective cohort study

Background: pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. Objective: to estimate the effectiveness of topical therapies in the treatment of PG. Methods: prospective cohort study of UK secondary care patients with a clinical diagnosis of PG suitable for topical treatment (recruited July 2009 to June 2012). Participants received topical therapy following normal clinical practice (mainly Class I-III topical corticosteroids, tacrolimus 0.03% or 0.1%). Primary outcome: speed of healing at 6 weeks. Secondary outcomes: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality-of-life; treatment failure and recurrence. Results: Sixty-six patients (22 to 85 years) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28/66 (43.8%) of ulcers healed by 6 months. Median time-to-healing was 145 days (95% CI: 96 days, ∞). Initial ulcer size was a significant predictor of time-to-healing (hazard ratio 0.94 (0.88;80 1.00); p = 0.043). Four patients (15%) had a recurrence. Limitations: No randomised comparator Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone

The Genetic and Environmental Determinants of Benign Melanocytic Naevi

Abstract for thesis entitled 'The genetic and environmental determinants ofbenign melanocytic naevi' submitted by Dr Rachel Caroline Wachsmuth for the degree of Doctor of Medicine 2006. The work covered in this thesis contributes to our understanding ofthe relationships between genes, sun exposure, benign melanocytic naevi and melanoma. Rare families with multiple cases of melanoma have been found to possess mutations in a limited number of genes, the first of which to be identified being CDKN2A (on chromosome 9p) that codes for the cell cycle regulating protein: p16. Epidemiological studies have shown that melanoma is a disease primarily of Caucasians who are at even greater risk with increased sun exposure. Furthermore, individuals with numerous benign melanocytic naevi are at increased risk ofmelanoma both in melanoma families and the general population. A combination of sun exposure and genes defining general and naevus phenotype is therefore key to the development of melanoma. In the first part of this thesis I examine the relationships between CDKN2A mutation status, --- --- ---:-----nae\ilisphe-riotype -ana presence of melanom-a,-inastuCly of 5-UK-iriehirioma-families. -I----- demonstrate a naevogenic role for CDKN2A, but a lack of absolute correlation between general naevus phenotype and CDKN2A genotype. I also estimate the penetrance ofCDKN2A mutation for melanoma within these families. I conClude that the practice oftargeting individuals with many naevi as potential gene carriers is untenable for melanoma screening purposes. In the second and main part of this thesis I examine the role ofgenes and sun exposure on the development of benign naevi in a twin study of221 UK twin pairs. In agreement with published literature, naevi were more common in males, persons with fairer skintypes or blue eyes, and in continuously sun exposed body sites compared to intermittently or non-exposed sites. Heritability analysis assessed genetic and environmental effects on naevus development and estimated that 26% of the variation in naevus counts between individuals was due to environmental effects (one third of which is hot holiday sun exposure), 3% to age and sex, 6% to measurement error and 65% due to genetic effects. Variation in naevus number is thus predominantly genetically inherited with a further breakdown ofthis 65% into 7% associated with eye colour, 6% with hair colour, I% with skintype and 51% with as yet unidentified 'naevus genes'. Such naevus genes may represent more common but lower penetrant melanoma genes than those identified to date. The previously mentioned CDKN2A gene was studied as a possible naevus gene by linkage analysis, but found not to associate with naevus counts. Further gene studies are therefore required to identify these naevus genes.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Jazz The Known: Artistic Experiments on Women of the ’20s

Jazz The Known: Artistic Experiments on Women of the ’20s. Co-organised with the Goethe-Institut, Ines Weizman, the Royal College of Art and Belmacz gallery. An evening of conversations on the occasion of Belmacz's group exhibition Women of the ’20s, at the Goethe-Institut London, including artists, curators, historians and theorists of art and architecture. Through a series of dynamic relays, this expanded conversation aimed to reflect on artistic practices that ‘jazz’ the known, in order to make sensible occluded ways of being

Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations

Patients with a family history of melanoma are at increased risk of this tumor. Those family members who also have the atypical mole syndrome are commonly targeted for screening in the belief that they are more likely to be mutant gene carriers. We have correlated the atypical mole syndrome phenotype and gene carrier status in five families with germline CDKN2A mutations and shown that family members with the atypical mole syndrome were three times more likely to be mutant gene carriers than their relatives who did not have the atypical mole syndrome (odds ratio 3.4; confidence interval 1.0-11.1), supporting the view that CDKN2A is nevogenic. Individual characteristics which best predicted mutant gene carrier status were: nevi on the buttocks (odds ratio 4.4; confidence interval 1.6-12.4), nevi on the feet (odds ratio 4.2; confidence interval 1.4-12.5), total nevus number being at least 100 (nevi ≥ 2 mm in diameter) (odds ratio 3.4; confidence interval 1.0-1.1) and two or more clinically atypical nevi (odds ratio 3.1; confidence interval 1.1-9.0). Gene carriers were also significantly more likely to have noticeable freckling and possibly also Fitzpatrick skin types 1-3. The overlap between gene carriers and nongene carriers was, however, marked: the atypical mole syndrome did not clearly differentiate mutant gene carriers from those with a normal gene. This study is of significance to clinicians as the clinical practice of using the atypical mole syndrome to identify particular family members for surveillance is shown to be inappropriate. Until formal gene testing is available, all members of families with an excessive number of melanoma cases should be treated as potential mutation carriers at increased risk of melanoma

Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study

Risk factors for melanoma include environmental (particularly ultraviolet exposure) and genetic factors. In rare families, susceptibility to melanoma is determined by high penetrance mutations in the genes CDKN2A or CDK4, with more common, less penetrant genes also postulated. A further, potent risk factor for melanoma is the presence of large numbers of melanocytic nevi so that genes controlling nevus phenotype could be such melanoma susceptibility genes. A large Australian study involving twins aged 12 y of predominantly U.K. ancestry showed strong evidence for genetic influence on nevus number and density. We carried out essentially the same study in the U.K. to gain insight into gene-environment interactions for nevi. One hundred and three monozygous (MZ) and 118 dizygous (DZ) twin pairs aged 10-18 y were examined in Yorkshire and Surrey, U.K. Nevus counts were, on average, higher in boys (mean = 98.6) than girls (83.8) (p = 0.009) and higher in Australia (110.4) than in the U.K. (79.2, adjusted to age 12 y, p < 0.0001), and nevus densities were higher on sun-exposed sites (92 per m(2)) than sun-protected sites (58 per m(2)) (p < 0.0001). Correlations in sex and age adjusted nevus density were higher in MZ pairs (0.94, 95% CI 0.92-0.96) than in DZ pairs (0.61, 95%CI 0.49-0.72), were notably similar to those of the Australian study (MZ = 0.94, DZ = 0.60), and were consistent with high heritability (65% in the U.K., 68% in Australia). We conclude that emergence of nevi in adolescents is under strong genetic control, whereas environmental exposures affect the mean number of nevi

Genome-wide association study identifies three novel susceptibility loci for severe <em>Acne vulgaris</em>

Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Here we perform a genome-wide association analysis in the United Kingdom, comparing severe cases of acne (n=1,893) with controls (n=5,132). In a second stage, we genotype putative-associated loci in a further 2,063 acne cases and 1,970 controls. We identify three genome-wide significant associations: 11q13.1 (rs478304, Pcombined=3.23 × 10−11, odds ratio (OR)=1.20), 5q11.2 (rs38055, Pcombined=4.58 × 10−9, OR=1.17) and 1q41 (rs1159268, Pcombined=4.08 × 10−8, OR=1.17). All three loci contain genes linked to the TGFβ cell signalling pathway, namely OVOL1, FST and TGFB2. Transcripts of OVOL1 and TFGB2 have decreased expression in affected compared with normal skin. Collectively, these data support a key role for dysregulation of TGFβ-mediated signalling in susceptibility to acne