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Biomedical subjects

M J Cork

Publications and source records attributed to M J Cork.

At least 19 recordsLinked to original sources
PubMed2004

Genetic association between an AACC insertion in the 3'UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis.

Atopic dermatitis is a disease with an impaired skin barrier that affects 15%-20% of children. In the normal epidermis, the stratum corneum chymotryptic enzyme (SCCE) thought to play a central role in desquamation by cleaving proteins of the stratum corneum (e.g., corneodesmosin and plakoglobin). Genetic variations within the SCCE gene could be associated with dysregulation of SCCE activity leading to an abnormal skin barrier. We screened the SCCE gene for variations and performed a case-control study on 103 atopic dermatitis patients and 261 matched controls. 16 synonymous single nucleotide polymorphisms (SNPs) have been identified and a 4 bp (AACC) insertion has been found in the 3'UTR. We performed an association study of the SCCE AACC insertion in the 3'UTR, and found a significant trend between the AACC allele with the two insertions and disease in the overall data set [odds ratio (OR)=2.31; p=0.0007]. The AACC insertion in the SCCE gene may result in a change to SCCE activity within the skin barrier. These findings suggest that SCCE could have an important role in the development of atopic dermatitis.

3' Untranslated Regions↗
PubMed2003

Notch4, a non-HLA gene in the MHC is strongly associated with the most severe form of alopecia areata.

Alopecia areata (AA) is a disorder primarily affecting the hair and nails in which associated autoimmune or atopic disease is common. Genetically, it is a complex trait with evidence of a role for genes of the major histocompatibility complex (MHC), the interleukin-1 cluster and chromosome 21 in the pathogenesis. The strongest association is with HLA class II alleles, although whether this indicates a direct contribution to the pathogenesis or results merely from linkage disequilibrium with nearby disease genes is unknown. Notch4 is a recently defined gene in the HLA class III region. Notch signalling is a direct determinant of keratinocyte growth arrest and entry into differentiation. A possible role for Notch in hair growth has been indicated by transgenic mouse findings that activation of the Notch pathway in the hair cortex leads to aberrant differentiation of adjacent hair-shaft layers. Notch4 is therefore a plausible candidate gene for AA. We have examined two polymorphisms in the coding sequence of the Notch4 gene at positions +1297 and +3063 in a case-control study of 116 AA patients and 142 ethnically matched, healthy control subjects. The initial analysis showed a significant association of AA in the overall data set with the Notch4(T+1297C) polymorphism (P<0.001) but not with Notch4(A+3063G). To confirm this association, we genotyped an additional 62 patients and found that the risk for disease was higher in Notch4(+1297C) homozygotes [odds ratio (OR) 3.43 (1.63, 7.19)] than in heterozygotes [OR 2.58 (1.57, 4.24)]. On classifying the patients by severity of disease, the association appeared to be confined to the severest form (alopecia universalis) [OR 4.02 (1.64, 9.88), P=0.0014]. These results support previous findings showing that different HLA susceptibility alleles are associated with mild and severe AA.

Alleles↗
PubMed2003

Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse.

BACKGROUND: The failure of patients to take medicines in a way that leads to clinical benefit is a major challenge. A consensus has emerged that, on average, compliance sufficient to obtain therapeutic objectives occurs about half the time, with noncompliance contributing to therapeutic failure in the other half. These figures refer to simple oral regimens. There has been little work assessing compliance/concordance with complex treatment regimens for atopic eczema. Asthma schools led by specialist nurses have been shown to improve knowledge, use of therapies and clinical outcome. OBJECTIVES: To determine the effect of education and demonstration of topical therapies by specialist dermatology nurses on therapy utilization and severity of atopic eczema. METHODS: Fifty-one children with atopic eczema attending a paediatric dermatology clinic were followed for up to 1 year. At each visit the parent's knowledge about atopic eczema and its treatment and therapy utilization was recorded. The severity of the eczema was recorded using the six area, six sign atopic dermatitis severity score (SASSAD) and parental assessment of itch, sleep disturbance and irritability. At the first visit a specialist dermatology nurse explained and demonstrated how to use all of the topical treatments. This education was repeated at subsequent visits depending on the knowledge of the parent. RESULTS: At baseline less than 5% of parents had received/recalled receiving any explanation of the causes of eczema or demonstration of how to apply topical treatments. The eczema was poorly controlled in all children (mean SASSAD 42.9). Of the children, 24% were not being treated with any emollient cream/ointment; the mean use was 54 g weekly. Of the children, 25% were being inappropriately treated with potent or very potent topical steroids. Following repeated education and demonstration of topical therapies by a specialist dermatology nurse, there was an 89% reduction in the severity of the eczema. The main change in therapy utilization was an 800% increase in the use of emollients (to 426 g weekly of emollient cream/ointment) and no overall increase in the use of topical steroids, accounting for potency and quantity used. CONCLUSIONS: This study reinforces the importance of specialist dermatology nurses in the management of atopic eczema. It also confirms the opinion of patients, patient support groups, dermatologists and best practice guidelines that the most important intervention in the management of atopic eczema is to spend time to listen and explain its causes and demonstrate how to apply topical therapies.

Administration, Topical↗
PubMed2003

Eumovate (clobetasone butyrate 0.05%) cream: a review of clinical efficacy and safety.

Topical steroid creams and ointments have been available as over-the-counter (OTC) medications for the self treatment of acute dermatitis and other steroid responsive skin disorders for more than ten years. Despite earlier fears, widespread availability and use of these creams is not associated with clinically significant adverse effects. In dermatological practice, hydrocortisone 1% remains the mainstay of treatment for facial eczema, but it is often not effective in eczema affecting other body areas. Eumovate(TM) (clobetasone butyrate 0.05%) cream has recently been made available as a pharmacy medication for the short-term management of acute eczema and allergic dermatitis by adults and children aged 10 or older, based on evidence derived from clinical trials involving over 3500 patients. This review summarises the key efficacy and safety data derived from 29 clinical trials and the post-licensing pharmacovigilance safety information, which supported the reclassification of this product for OTC use. These data show clobetasone butyrate 0.05% is more effective than 1.0% hydrocortisone in the treatment of eczema and more effective than flurandrenolone 0.0125% (p=0.01%) and a potent topical steroid hydrocortisone butyrate (p<0.05), in the treatment of psoriasis. A review of the effect of topical steroids on skin thickness concluded that, following short term application, there was no clinically significant difference between hydrocortisone 1.0% and clobetasone butyrate 0.05% in terms of potential for skin thinning. Similarly, even under extreme conditions, clobetasone butyrate 0.05% has negligible systemic absorption and has almost no effect on HPA axis function.

Acute Disease↗
PubMed2002

Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis.

Alopecia areata is characterized by a reversible form of patchy or complete hair loss associated with T-cell infiltration of hair follicles. The lifetime disease risk of approximately 1.4% in the general population is increased to more than 30% in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome (APECED), a recessive condition resulting from a mutation of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. Aire protein is thought to have transcriptional regulatory activity but its role is not well defined at present. In this study, we have examined the possible involvement of AIRE in the pathogenesis of alopecia areata. On screening the AIRE coding sequence, we identified 20 variants. Two of these at positions, G961C and T1029C, give rise to amino acid changes, S278R and V301A, located in the DNA-binding segment (SAND) and PHD1 zinc finger motif, respectively. We found no difference in the frequency of the AIRE T1029C polymorphism between the control and patient groups. We genotyped 202 alopecia areata patients and 175 matched Caucasian controls for the AIRE G961C alleles. The frequency of the rare allele (961G) was 0.08 in the controls and there was a significant increase to 0.13 in alopecia areata overall and 0.20 in severe disease (alopecia universalis). We found no association between the AIRE G961G variant and mild (patchy) alopecia areata or alopecia totalis. However, the AIRE 961G allele is a potent risk factor (> 3) for the severest form of alopecia areata, and for disease of early age at onset (at 30 years). The change from serine to arginine in the SAND domain of AIRE protein may have a significant effect on AIRE DNA-binding activity. Moreover, our results could provide a rational explanation of the unusually high frequency of AA in APECED patients, supporting the concept of AA as an autoimmune disease.

Adolescent↗
PubMed2002

Topical preparations for the treatment of psoriasis: a systematic review.

BACKGROUND: There is clinical uncertainty about the appropriate use of first-line topical treatments for psoriasis. OBJECTIVES: To assess the relative effectiveness and tolerability of topical treatments for psoriasis suitable for use both in primary and secondary care. METHODS: All major medical databases of published literature were searched electronically; references of trial reports and recent reviews were searched; authors and companies were contacted for missing data from published reports. The study selection comprised: (1) randomized placebo-controlled trials of topical treatments for psoriasis; and (2) randomized head-to-head studies of the new vitamin D3 derivative treatments for psoriasis that reported clinical outcome using a Total Severity Score (TSS), Psoriasis Area Severity Index or Investigator Assessment of Global Improvement. Eligibility and validity were assessed and data extracted independently by two authors. Clinical outcomes were pooled using a random effect standardized weighted mean difference (SWMD) metric, including 3380 patients randomized in 41 placebo (vehicle)-controlled trials and 4898 patients randomized in 28 head-to-head studies. RESULTS: There was a significant benefit in favour of active treatments against vehicle, SWMD: -1.06 (95% confidence interval [CI]: -1.26 to -0.86), approximately a 2-point improvement on a 12-point TSS after 6-8 weeks of treatment. The only significantly different benefit was for very potent corticosteroids: SWMD: -1.51 (95% CI: -1.76 to -1.25), approximately a 3-point improvement on a 12-point TSS. Head-to-head studies support these findings, except that calcipotriol was estimated to be more effective than dithranol, coal tar and other vitamin D3 derivatives. Polytherapy, using a potent steroid and calcipotriol, was more effective than calcipotriol alone: SWMD 0.42 (95% CI: 0.12-0.72 ) approximately a 0.8-point improvement on a 12-point TSS. No important differences in withdrawal or reporting of adverse events were identified. CONCLUSIONS: Trials of short duration neither adequately inform the management of chronic disease nor describe the sequelae of treatment. The evidence base for long-term care, reflecting the disease pathway, should be improved. Combination therapy with topical vitamin D analogues and steroids, and maintenance therapy following treatment response merit further investigation.

Administration, Cutaneous↗
PubMed2002

Genetic analysis of the interleukin-1 receptor antagonist and its homologue IL-1L1 in alopecia areata: strong severity association and possible gene interaction.

Alopecia areata is an inflammatory hair loss disease with a major genetic component. The presence of focal inflammatory lesions with perifollicular T-cell infiltrates reflects the importance of local cytokine production in the pathogenesis. In addition to its fundamental pro-inflammatory role, the interleukin-1 (IL-1) system has major effects on hair growth regulation in vitro, with the inhibitory actions of IL-1alpha and IL-1beta being opposed by the receptor antagonist IL-1ra. The novel interleukin-1 like molecule 1 (IL-1L1) which has greatest gene sequence homology with IL1RN, the gene encoding IL-1ra, is another potential IL-1 antagonist. In view of previous studies suggesting a significant role for IL1RN polymorphisms in the pathogenesis of autoimmune/inflammatory disease, we have analysed polymorphisms of IL-1ra (IL1RN+2018) and its homologue IL-1L1 (IL1L1+4734) in a case-control association study on 165 patients and a large number of matched controls. Homozygosity for the rare allele of IL1RN (IL1RN*2) was significantly associated with alopecia areata [odds ratio (OR) = 1.89, 95% CI (1.09, 3.28); P = 0.02], confirming our previous findings of significant association with the IL1RN variable number tandem repeat (VNTR). The results also revealed a novel association involving a polymorphism of the interleukin-1 receptor antagonist homologue IL1L1 at position + 4734, IL1RN+2018, and alopecia areata. The effect of a genotype combining three copies of the rare alleles at the IL1RN and IL1L1 loci conferred a more than additive increase in the risk of disease compared to IL1RN+2018 or IL1L1+4734 alone [OR 3.37 (1.60, 7.06); P = 0.002], suggesting possible synergy between the IL1RN and IL1L1 genes. This effect was stronger in patients with severe disease (alopecia totalis/universalis) [OR 4.62 (1.87, 11.40), P = 0.0022], and in those with early age at onset (< 20 years) [OR = 6.38 (2.64, 15.42), P = 0.0002]. Our results suggest that these polymorphisms within IL1RN and IL1L1 themselves or a gene in linkage disequilibrium with IL1RN and IL1L1 predispose to the more severe forms of alopecia areata.

Adult↗
PubMed2001

Association analysis of IL1A and IL1B variants in alopecia areata.

Alopecia areata is an inflammatory hair loss disease with a major genetic component. The disease is characterized by focal inflammatory lesions with perifollicular T-cell infiltrates, reflecting the role of local cytokine production in the development of patchy hair loss. IL-1 alpha and IL-1 beta are important inhibitors of hair growth in vitro. Their effect is opposed by the interleukin-1 receptor antagonist, IL-1ra. Genes of the IL-1 cluster are candidate genes in the pathogenesis of alopecia areata. To investigate the role of the IL-1 system in alopecia areata we examined three biallelic polymorphisms within the IL-1 gene cluster (IL1A+4845, IL1B+3954 and IL1B-511) in 165 patients and a large number of matched controls (n=1150). There was no significant association of IL1B-511 or IL1B+3954 genotypes with the overall dataset, or with disease severity or age at onset, in contrast with a previous report. The results suggested the possibility of an association with IL1A+4845 in the overall dataset [OR 1.39 (95% CI 1.00, 1.93)] although this was not statistically significant. This was due mainly to the contribution from mild cases of alopecia areata [OR 1.48 (0.96, 2.29)], suggesting that IL-1 alpha may have a particular role in the pathogenesis of this subgroup.

Adult↗
PubMed2000

Structure and polymorphism of the human gene for the interferon-induced p78 protein (MX1): evidence of association with alopecia areata in the Down syndrome region.

Alopecia areata (AA) is a chronic inflammatory disease characterised by patchy hair loss with T cell infiltration of hair follicles. AA occurs in approximately 0.1% of the general population, but this is increased to 9% in Down syndrome (DS). DS is associated with an additional copy (full or partial) of chromosome 21, and the DS region may potentially include genes involved in the pathogenesis of AA. MX1 is the gene encoding the interferon-induced p78 protein (MxA). MxA protein confers resistance to influenza viruses, and we have previously shown that MxA protein is strongly expressed in lesional anagen hair bulbs from patients with AA but not in normal follicles. We therefore studied the possible involvement of MX1 in the pathogenesis of AA. To establish markers in the MX1 region which could be screened by PCR-based methods, we defined the human MX1 exon/intron organisation and screened the exons and the introns by conformation-sensitive gel electrophoresis. We found that the MX1 gene contains 17 exons extending over 33 kb. The size and sequence of the region from exon 6 to exon 16 are highly conserved between human and mouse. Screening of 4747 bp within the MX1 gene revealed four single nucleotide polymorphisms in intron 6. These polymorphisms are concentrated within 147 bp and show strong linkage disequilibrium. In a case-control association study for the MX1 (+9959) polymorphism in 165 AA patients and 510 controls we found a significant association of this marker with AA (odds ratio 1.79, 95% CI 1.21-2.66, chi2 = 8.464, P = 0.0036). The risk of disease was greater for patchy AA (mild disease) and with early age at onset (odds ratio 2.34, 95% CI 1.24-4.43, P = 0.0072), providing new evidence of genetic heterogeneity in AA. Our demonstration of genetic association between the MX1 gene and disease supports the hypothesis that this is a new candidate gene in AA.

Alopecia Areata↗
PubMed2000

Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy.

Cyclosporin (CyA) has been shown to be highly effective and well tolerated in the short-term treatment of severe childhood atopic dermatitis; however, there is limited experience in its longer-term use. The aim of this study was to compare multiple short courses of CyA with continuous therapy for 1 year, with respect to efficacy, safety, tolerability and quality of life. Children aged 2-16 years, with a diagnosis of severe atopic dermatitis refractory to topical steroid therapy, were randomly assigned to receive short course therapy (multiple courses of 12 weeks) or continuous therapy. The starting dose and maximum dose for all patients was 5 mg/kg per day. Disease activity was monitored using the Six Area Six Sign Atopic Dermatitis score and the 'Rule of Nines' area score. Pruritus, sleep disturbance and irritability were measured using visual analogue scales, and topical therapy was monitored. Safety measurements included monitoring of serum creatinine, blood pressure and adverse events. Forty patients were included in the efficacy analysis, 21 of whom were randomized to the short course group (of whom six were withdrawn) and 19 to the continuous group (of whom five were withdrawn). Significant improvements were seen in all efficacy parameters at every time-point. There were no significant differences between groups, although the improvement was more consistent in the continuous arm. In the short course arm, 7 out of 21 patients could be managed by at least two short courses. The remaining 14 patients includes 12 who could not be controlled by at least two short courses, one patient who failed to return after week 12 and another patient who was withdrawn at week 4 due to an adverse event. Quality of life improved for both the children and their families. Tolerability was considered good or very good in at least 80% of the patients at week 12 and at the end of the study. No clinically significant change was seen in mean serum creatinine and no change was seen in mean blood pressure in either group. CyA is effective in controlling severe atopic dermatitis in children over a 1-year period and is well tolerated. More consistent control is achieved with continuous treatment; however, short course therapy was adequate for some patients, indicating that treatment should be tailored to the individual patient's needs. Short course treatment may produce prolonged remission in some cases and reduce the cumulative exposure to the drug.

Adolescent↗
PubMed1999

Analysis of a microsatellite polymorphism of the cytotoxic T-lymphocyte antigen-4 gene in patients with vitiligo.

The CTLA-4 gene encodes a T-cell receptor that is involved in the regulation of T-cell activation. Recent studies have demonstrated an association of a microsatellite polymorphism [variant lengths of a dinucleotide (AT)n repeat] lying in exon 3 of the CTLA-4 gene, specifically a 106-bp allele, with autoimmune disorders, such as Graves' disease, autoimmune Addison's disease and autoimmune hypothyroidism. The aim of the present study was to determine whether the same polymorphism of the CTLA-4 gene was associated with vitiligo, a disorder that may have an autoimmune origin and can be present in patients who have one or more autoimmune diseases. CTLA-4 gene microsatellite polymorphisms were determined for 74 vitiligo patients (53 without any autoimmune disorder; 21 with one or more autoimmune disease) and 173 healthy controls, who had no clinical evidence of either vitiligo or any other autoimmune disorder, by polymerase chain reaction amplification of genomic DNA and resolution of the products on polyacrylamide sequencing gels. The frequency of the 106-bp allele was significantly increased (chi2 = 5. 2; P = 0.02) in vitiligo patients as a whole, in comparison with control subjects. However, when the patients were classified according to the absence or presence of an autoimmune disorder, the frequency of the 106-bp allele was significantly increased (chi2 = 14.8; P = 0.0001) only in the group of vitiligo patients who also had an autoimmune disease. However, the fact that 17 of 21 patients also had either autoimmune thyroiditis or autoimmune Addison's disease probably accounts for the apparent association of vitiligo and the 106-bp allele in this patient group. However, it was found that the relative risk of 3.2, conferred by the 106-bp allele in this group of vitiligo patients, was greater than that found for patients with only either Graves' disease, autoimmune hypothyroidism or autoimmune Addison's disease, with values of 2.1, 2.2 and 2.2, respectively. For the group of patients without an autoimmune disorder, there was no significant difference (chi2 = 0.2; P = 0.64) in the frequency of the 106-bp allele when compared with control subjects. These results indicate that there is no association between the 106-bp allele and vitiligo, at least when the disorder occurs in the absence of an autoimmune disease.

Abatacept↗
PubMed1999

Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis.

Psoriasis is an inflammatory skin disease of unknown origin, but with a clear genetic component. The strongest genetic association has been found with the major histocompatibility complex (MHC) region, and specifically between susceptibility to familial early onset psoriasis and human leukocyte antigen (HLA)-Cw6. The basis of this association of the HLA-C locus with disease pathogenesis is, however, not clear, and it is possible that other genes, or a combination of genes, in the HLA region are of functional importance. The MHC S gene is expressed specifically in keratinocyte differentiation and, being located 160 kb telomeric of HLA-C, is a plausible candidate gene. We analysed the allelic distribution of two polymorphisms in the MHC S gene (at +619 and +1243) in a case-control association study. We could confirm a significant association between psoriasis and HLA-Cw6 [odds ratio (OR) = 7.75]. No association was found between disease (or any subtypes) and the MHC S gene polymorphism at position +619, despite its close proximity to HLA-C and the strong linkage disequilibrium between the loci. However, a significant trend with the rarer allele at MHC S (+1243) and psoriasis was detected in the overall data set (OR = 2. 66; P = 2 [times] 10(-)9). This effect was most pronounced in the type 1a (early onset) psoriatics (OR = 3.43). Furthermore, homozygosity for the associated allele at MHC S (+1243) increased the risk of disease over that for carriage of HLA-Cw6 alone (OR = 9. 38), suggesting that allele 2 of MHC S (+1243) provides an additional risk in psoriasis susceptibility. The strong association found here, coupled with the biological involvement of the MHC S gene product corneodesmosin in skin physiology, implicates this locus (or a haplotype across HLA-C and MHC S ) in the impaired desquamation characteristic of psoriasis.

Adult↗
PubMed1998

A retrospective cost-effectiveness analysis of the treatment of onychomycosis in general practice.

Analysis of the computer records of 100 general practices from the CompuFile Doctors Independent Network revealed 1492 patients receiving treatment for onychomycosis in the first 6 months of 1994 with terbinafine, tioconazole, amorolfine or griseofulvin. These records indicated the average treatment time for each agent, number of general practitioner consultations and incidence of hospital referrals and minor surgery. Applying standard costs to this resource consumption gave the direct costs for each of these four agents. Published clinical and mycological cure rates allowed a cost per success to be calculated. These were as follows: terbinafine (n = 511) pound258, amorolfine (n = 315) pound312, griseofulvin (n = 196) pound356 and tioconazole (n = 470) pound520. Sensitivity analysis showed that terbinafine remained the most cost-effective option despite variations in resource costs. The cost impact on a typical practice for switching from a less to a more cost-effective treatment is discussed.

Antifungal Agents↗