| 1. |
- Chamcheu, Jean Christopher, et al.
(författare)
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Epidermolysis bullosa simplex due to KRT5 mutations : mutation-related differences in cellular fragility and the protective effects of trimethylamine N-oxide in cultured primary keratinocytes
- 2010
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Ingår i: British Journal of Dermatology. - : Wiley InterScience. - 0007-0963 .- 1365-2133. ; 162:5, s. 980-989
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Tidskriftsartikel (refereegranskat)abstract
- Summary Background Epidermolysis bullosa simplex (EBS) is a mechanobullous skin fragility disease characterized by cytolysis of basal keratinocytes and intraepidermal blistering often caused by mutations in keratin genes (KRT5 or KRT14). No remedies exist for these disorders presenting a need for development of novel therapies. Objectives To identify new genotype-phenotype relationships in vivo and in cultured primary EBS keratinocytes in vitro, and to study the cytoskeletal stabilizing effects of trimethylamine N-oxide (TMAO) in heat-stressed EBS cells. Methods Genomic DNA and cDNA samples from three Swedish patients with EBS were analysed for keratin mutations. Primary EBS keratinocyte cultures were established, heat stressed with and without added TMAO, followed by evaluation of cellular fragility. Results In addition to the previously reported KRT5 mutation (V186L) in one patient, two patients were found to have a novel I183M and recurrent E475G replacements in KRT5. Cultured EBS keratinocytes did not exhibit keratin aggregates or cell loss, except in the patient with the p.I183M mutation who showed 3% aggregates and 2% cell loss. Upon transient heat stress the number of aggregate-containing cells increased to 21%, 27% and 13%, respectively, in the p.I183M, p.E475G and p.V186L mutant cells. Interestingly, pretreatment with TMAO prior to heat stress, dose dependently reduced the number of aggregate-containing cells and cell loss. Conclusion These results revealed a genotype-phenotype correlation in EBS keratinocytes upon heat stress and suggest protein stabilization as a new therapeutic strategy.
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| 2. |
- Chamcheu, Jean Christopher, et al.
(författare)
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Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype : A useful in vitro model for testing new treatments
- 2011
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Ingår i: British Journal of Dermatology. - : British Association of Dermatologists. - 0007-0963 .- 1365-2133. ; 164:2, s. 263-272
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidermolytic ichthyosis (EI) is a skin fragility disorder caused by mutations in genes encoding suprabasal keratins 1 and 10. While the aetiology of EI is known, model systems are needed for pathophysiological studies and development of novel therapies. Objectives To generate immortalized keratinocyte lines from patients with EI for studies of EI cell pathology and the effects of chemical chaperones as putative therapies. Methods We derived keratinocytes from three patients with EI and one healthy control and established immortalized keratinocytes using human papillomavirus 16-E6/E7. Growth and differentiation characteristics, ability to regenerate organotypic epidermis, keratin expression, formation of cytoskeletal aggregates, and responses to heat shock and chemical chaperones were assessed. Results The cell lines EH11 (K1-p.Val176-Lys197del), EH21 (K10-p.156Arg>Gly), EH31 (K10-p.Leu161-Asp162del) and NKc21 (wild-type) currently exceed 160 population doublings and differentiate when exposed to calcium. At resting state, keratin aggregates were detected in 9% of calcium-differentiated EH31 cells, but not in any other cell line. Heat stress further increased this proportion to 30% and also induced aggregates in 3% of EH11 cultures. Treatment with trimethylamine N-oxide and 4-phenylbutyrate (4-PBA) reduced the fraction of aggregate-containing cells and affected the mRNA expression of keratins 1 and 10 while 4-PBA also modified heat shock protein 70 (HSP70) expression. Furthermore, in situ proximity ligation assay suggested a colocalization between HSP70 and keratins 1 and 10. Reconstituted epidermis from EI cells cornified but EH21 and EH31 cells produced suprabasal cytolysis, closely resembling the in vivo phenotype. Conclusions These immortalized cell lines represent a useful model for studying EI biology and novel therapies.
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| 3. |
- Hoppe, Torborg, et al.
(författare)
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X-linked recessive ichthyosis : an impaired barrier function evokes limited gene responses before and after moisturizing treatments
- 2012
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 167:3, s. 514-522
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Tidskriftsartikel (refereegranskat)abstract
- Background X-linked recessive ichthyosis (XLRI) is due to deletions or inactivating mutations in the steroid sulfatase (STS) gene. This results in an accumulation of cholesterol sulphate affecting the packing of intercorneocyte lipids. XLRI is characterized by dry, scaly skin and increased skin barrier permeability; patients are often dependent on daily use of moisturizers.Objectives To examine the biophysical and molecular changes in the skin of patients with XLRI compared with healthy volunteers, and to analyse the effects of moisturizers on the patients' barrier function.Methods Patients with XLRI (n = 14) and healthy controls (n = 14) were included in the study. Skin dryness score, transepidermal water loss (TEWL) and skin surface pH were monitored at baseline, and punch biopsies were obtained for mRNA expression profiles determined by oligonucleotide arrays. Measurements were repeated in the patients with XLRI after a 4-week treatment with three different moisturizers on the volar forearms. Results Patients with XLRI showed, compared with healthy controls, increased dryness and TEWL, equal skin pH and altered expression of 27 genes. There were no signs of activation of inflammation or repair pathways. Five selected genes were significantly altered also on quantitative polymerase chain reaction analysis. Treatment with the moisturizers showed similar effects: they improved skin dryness but had no effect on TEWL, pH or expression of selected genes.Conclusions Despite a dysfunctional skin barrier, the limited number of genes altered in XLRI skin suggests that no inflammatory or repair mechanisms are triggered. Treatment with moisturizers does not have any major impact on the skin barrier properties of patients with XLRI.
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| 4. |
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| 5. |
- Mazereeuw-Hautier, J., et al.
(författare)
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Management of congenital ichthyoses : European guidelines of care, part two
- 2019
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Ingår i: British Journal of Dermatology. - : WILEY. - 0007-0963 .- 1365-2133. ; 180:3, s. 484-495
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Tidskriftsartikel (refereegranskat)abstract
- These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert-based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis. What's already known about this topic? Various symptomatic treatment options exist for congenital ichthyoses, but there are no European guidelines. What does this study add? These European guidelines for the management of congenital ichthyosis may help to improve outcomes and quality of life for patients. Linked Comment: Akiyama. Br J Dermatol 2019; 180:449-450. Plain language summary available online
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| 6. |
- Mazereeuw-Hautier, J., et al.
(författare)
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Management of congenital ichthyoses : European guidelines of care, part one
- 2019
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 180:2, s. 272-281
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Tidskriftsartikel (refereegranskat)abstract
- These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016 and a consensus on the discussions. They summarize evidence and expert-based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling.
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| 7. |
- Pavez Loriè, Elizabeth, et al.
(författare)
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Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis
- 2009
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 160:1, s. 26-36
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: An alternative approach to retinoid therapy is to inhibit the cytochrome P450 (CYP)-mediated catabolism of endogenous all-trans retinoic acid in the skin by applying retinoic acid metabolism blocking agents such as talarozole (R115866). OBJECTIVES: To study the effects of topical talarozole on retinoid biomarkers in normal skin in a randomized phase I trial. METHODS: Gels containing talarozole (0.35% or 0.07%) and vehicle were applied once daily for 9 days on either buttock of 16 healthy volunteers. Epidermal shave biopsies (for mRNA analysis) and punch biopsies (for histology and immunofluorescence analysis) were collected from the treatment areas. Genes encoding the following were studied by quantitative real-time polymerase chain reaction: cellular retinoic acid binding protein 2 (CRABP2), cytokeratins (KRT2 and KRT4), CYP26A1, CYP26B1, CYP26C1 and CYP2S1, two enzymes in the retinol metabolism (retinal dehydrogenase-2 and retinol acyltransferase) and two proinflammatory cytokines [interleukin (IL)-1alpha and tumour necrosis factor-alpha]. RESULTS: Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1 dose dependently, and decreased the expression of KRT2 and IL-1alpha compared with vehicle-treated skin. No mRNA change in retinol-metabolizing enzymes was obtained. There was no induction of epidermal thickness or overt skin inflammation in talarozole-treated skin. Immunofluorescence analysis confirmed an upregulation of KRT4 protein, but no upregulation of CYP26A1 and CYP26B1 expression was detected. CONCLUSIONS: Talarozole influences the biomarker pattern consistently with increased retinoic acid stimulation. The low irritancy of talarozole at the two examined dosages is a possible advantage over topical retinoids.
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| 8. |
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| 9. |
- Swartling, Carl, et al.
(författare)
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Botulinum toxin in the treatment of sweat-worsened foot problems in patients with epidermolysis bullosa simplex and pachyonychia congenita
- 2010
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 163:5, s. 1072-1076
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Tidskriftsartikel (refereegranskat)abstract
- Background: Painful foot blistering is a common problem in patients with epidermolysis bullosa simplex (EBS) and pachyonychia congenita (PC). Hyperhidrosis, a condition which can be effectively blocked by plantar injections of botulinum toxin (Btx), often exacerbates the blistering. Objectives: A retrospective evaluation of the effects of Btx injections in 14 EBS and PC patients with foot blisters and painful callosities. Patients/methods: After informed consent, patients with EBS (n=6) and PC (n=8), aged 7-66 years, who had received Btx therapy at our centre since 2003, were included. The treatment consisted of multiple plantar injections of Btx A or Btx B after prior regional or general anaesthesia. Patients were interviewed about the treatment effect and were asked to score the improvement from 0-5, where 5 is 'excellent'. One PC patient with painful callosities was studied by magnetic resonance (MR) spectroscopic micro-imaging technique before and after Btx injections to disclose any underlying blisters. Results: A total of 76 treatments were evaluated (1-19 sessions/patient). Thirteen patients (92.8%) reported reduced plantar blistering and pain; the improvement score was >/=4 in 4/6 EBS patients and 6/8 PC patients. The mean effect duration was 3 months. No adverse events, apart from mild anti-cholinergic side-effects in 2 patients, were noted. MR spectroscopic micro-imaging showed disappearance of intraepidermal blistering after Btx therapy. Conclusions: Plantar injection of Btx is an efficient, long-lasting and safe treatment of painful blistering and callosities in EBS and PC that can be given repeatedly without loss of efficacy.
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| 10. |
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