Fumaric acid esters for severe psoriasis: the Leicestershire experience.
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Adult↗
Biomedical subjects
J E Osborne
Publications and source records attributed to J E Osborne.
Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis.
Psoriasis is a genetically determined disease characterized by hyperproliferation and disordered maturation of the epidermis. Th1 lymphocytes are implicated in its pathogenesis. The vitamin D receptor (VDR) is a candidate modifying gene, having immunosuppressive effects and being involved in anti-proliferative and pro-differentiation pathways in keratinocytes. There is suggestive evidence that the A allele of the A-1012G polymorphism is associated with down-regulation of the Th1 response, via GATA-3. The F and T alleles of Fok1 and Taq1 have been associated with increased VDR activity. The present study aimed to test the hypothesis that the A allele of A-1012G is protective for occurrence and severity of psoriasis and enhances therapeutic response to vitamin D analogues and that these effects would be additive to those of Fok1 and Taq1. The study group comprised 206 psoriasis patients who had received topical calcipotriol treatment and 80 controls. There was no significant linkage disequilibrium between any pair of the three polymorphic sites (P=0.3-0.8). The A, F and T alleles were positively associated with calcipotriol response: AA genotype (compared to AG/GG), odds ratio (OR)=2.18 (P=0.04); TT, OR=1.97 (P=0.03); AAFF genotype combination, OR=4.11 (P=0.03); AATT, OR=5.64 (P=0.005); and FFTT, OR=3.22 (P=0.01). Comparing patients without, to patients with, a family history of psoriasis, the A allele was under represented (P=0.01) and the AAFF genotype combination even more so (compared to residual genotypes) (OR=0.24; P=0.005). AAFF was also under-represented in patients without a family history compared to controls (OR=0.31; P=0.04). There were no associations of family history with Fok1 and Taq1. There were no associations of severity of psoriasis with any polymorphism. In conclusion, the A-1012G, Fok1 and Taq1 VDR polymorphisms were associated with response to calcipotriol. A-1012G and Fok1 were associated with susceptibility to non-familial psoriasis.
Adolescent↗
Longitudinal melanonychia and pseudo-Hutchinson sign associated with amlodipine.
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Aged↗
A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibilty and prognosis in malignant melanoma.
The association of Taq 1 and Fok 1 restriction fragment length polymorphisms of the vitamin D receptor with occurrence and outcome of malignant melanoma (MM), as predicted by tumour (Breslow) thickness, has been reported previously. We now report a novel adenine-guanine substitution -1012 bp relative to the exon 1a transcription start site (A-1012G), found following screening by single-stranded conformational polymorphism of this promoter region. There was a total of 191 MM cases, which were stratified according to conventional Breslow thickness groups, cases being randomly selected from each group to form a distribution corresponding to the known distribution of Breslow thickness in our area, and this population (n=176) was compared to 80 controls. The A allele was over-represented in MM patients and, with GG as reference, odds ratio (OR) for AG was 2.5, 95% confidence interval (CI) 1.1-5.7, (P=0.03) and AA 3.3, CI 1.4-8.1, (P=0.007). The outcome was known in 171 of 191 patients and the A allele was related to the development of metastasis, the Kaplan-Meier estimates of the probability of metastasis at 5 years being: GG 0%; AG 9%, CI 4-16%; AA 21%, CI 12-36%; (P=0.008), and to thicker Breslow thickness groups (P=0.04). The effect on metastasis was independent of tumour thickness and A-1012G may have predictive potential, additional to Breslow thickness. Neither the Fok 1 nor Taq 1 variants (f and t) were significantly related to the development of metastasis, although there was a strong relationship of fftt with the thickest Breslow thickness group (P=0.005). There was an interaction between the A-1012G and Fok 1 polymorphisms (P=0.025) and the Fok 1 variant enhanced the effect of the A allele of the A-1012G polymorphism on metastasis, the probability of metastasis for AAff at 5 years follow-up being 57%, CI 24-92%.
DNA Mutational Analysis↗
Hijacking epidermal growth factor receptors by angiotensin II: new possibilities for understanding and treating cardiac hypertrophy.
Activation of the type 1 angiotensin II receptor (AT(1)R) is associated with the aetiology of left ventricular hypertrophy, although the exact intracellular signalling mechanism(s) remain unclear. Transactivation of the epidermal growth factor receptor (EGFR) has emerged as a central mechanism by which the G protein-coupled AT(1)R, which lacks intrinsic tyrosine kinase activity, can stimulate the mitogen-activated protein kinase signalling pathways thought to mediate cardiac hypertrophy. Current studies support a model whereby AT(1)R-dependent transactivation of EGFRs on cardiomyocytes involves stimulation of membrane-bound metalloproteases, which in turn cleave EGFR ligands such as heparin-binding EGF from a plasma membrane-associated precursor. Numerous aspects of the 'triple membrane-passing signalling' paradigm of AT(1)R-induced EGFR transactivation remain to be characterised, including the identity of the specific metalloproteases involved, the intracellular mechanism for their activation and the exact EGFR subtypes required. Here we examine how 'hijacking' of the EGFR might explain the ability of the AT(1)R to elicit the temporally and qualitatively diverse responses characteristic of the hypertrophic phenotype, and discuss the ramifications of delineating these pathways for the development of new therapeutic strategies to combat cardiac hypertrophy.
Angiotensin II↗
Comparison of diagnostic accuracy for cutaneous malignant melanoma between general dermatology, plastic surgery and pigmented lesion clinics.
BACKGROUND: Since the 1980s there have been dedicated pigmented lesion clinics (PLCs) in the U.K. Important considerations when comparing the efficacy of the PLC with other referral clinics include diagnostic accuracy. OBJECTIVES: To compare the false-negative rate of clinical diagnosis (FNR) in the PLC with that in the other clinics of primary referral of malignant melanoma (MM) in the same geographical area. We have previously shown that certain clinical features are risk factors for diagnostic failure of MM. A further aim of this study was to correct for any differences in frequency of these factors in the melanoma populations between clinics and to estimate the false-positive diagnostic rate (FPR) in the PLC. METHODS: To compare the FNR between clinics, the case notes of all patients presenting with histologically proven cutaneous MM in Leicestershire between 1987 and 1997 were examined retrospectively. A false-negative diagnosis was defined as documentation of another diagnosis and/or evidence in the case notes that the diagnosis was not considered to be MM. The FNR was estimated as the number of false-negative clinical diagnoses/number of true-positive histological diagnoses. To estimate the diagnostic FPR, which was defined as the number of false-positive clinical diagnoses of MM/total number of positive clinical diagnoses, in the PLC, the outcome of 500 consecutive patients attending the PLC was surveyed. RESULTS: The case notes of 731 patients were available, of whom approximately two-thirds initially attended the PLC, one-fifth the General Dermatology clinics (D) and the remainder were divided approximately equally (one-twentieth each) between Plastic Surgery clinics (P), other clinics (O) and the surgery of the general practitioner (GP). The last was regarded as the primary referral clinic if the lesion were excised there prior to any referral. The FNR was lowest for the PLC, at 10%, compared with 29% (D), 19% (P), 55% (O) and 54% (GP) (P < 0.0001). Lesions with risk factors for diagnostic failure were under-represented in the PLC (P < 0.0001), the mean frequencies of the risk factors being 20% (PLC), 25% (D), 22% (P), 31% (O) and 30% (GP). Differences were not large but still could partially explain the lower FNR of the PLC. However, when the FNR was estimated for lesions exhibiting each of these risk factors, the PLC was found to have the lowest rate in every case (PLC vs. all clinics combined, P = 0.04 to P < 0.0001). The mean FNR for the risk factors combined was 18% (PLC), 45% (D), 50% (P), 68% (O) and 71% (GP). Also on logistic multivariable analysis of the PLC vs. all the other clinics on FNR and the above factors, the higher FNR of the other clinics retained significance (odds ratio 5.9, P < 0.0001). In the 500 patients surveyed separately in the PLC, the MM pick-up rate on biopsy was 32% and the diagnostic FPR was 41%. CONCLUSIONS: The FNR of MM was lower in the PLC than in the other clinics, while the pick-up rate for MM on biopsy and the FPR were acceptably low.
Aged↗
Palatal surgery for snoring: objective long-term evaluation.
Snoring surgery has mainly been assessed in the literature using subjective outcome measures with some evidence to indicate that the benefits of surgery are short lived. There is remarkably little published on the objective outcome of snoring surgery. We reported previously short-term (2-11 months) objective results on 38 patients who had palatal surgery. All the patients had preoperative and postoperative objective assessment of their snoring loudness and duration in the home. The current study presents the long-term objective results of 24 patients from the same cohort. All patients who were included in our study had palatal snoring confirmed on sleep nasendoscopy. and none of them had significant obstructive sleep apnoea. The median follow-up period was 45 months (range 29-56 months). Overall, the mean snore index (SI) at long-term follow-up was significantly less than the preoperative SI (P < 0.0001). There was no significant difference between the short-term and the long-term results regarding the fall in the SI. This study is the first to use postoperative objective assessment in the home and to demonstrate that snoring reduction is maintained for several years after snoring surgery.
Endoscopy↗
Ischaemic necrosis and facial palsy in Warthin's tumour of the parotid gland.
A 72-year-old patient with a Warthin's tumor of the right parotid gland developed massive necrosis of the tumour associated with temporary facial palsy with subsequent macroscopic tumour disappearance.
Adenolymphoma↗
Temporomandibular joint dysfunction following tonsillectomy.
We report a prospective, controlled trial to assess temporomandibular joint (TMJ) dysfunction following the use of a Boyle-Davis mouth gag during tonsillectomy. TMJ function was evaluated in patients undergoing tonsillectomy and a control group undergoing nasal surgery preoperatively and 6 weeks postoperatively. The main outcome measures were symptoms and signs of TMJ dysfunction and interincisal distance. A mean reduction of 0.89 mm in interincisal distance (P < 0.01) was noted postoperatively in the tonsillectomy patients. There was no statistically significant reduction of interincisal distance in patients undergoing nasal surgery. There was a statistically significant reduction in interincisal distance in the post-tonsillectomy patients, caused by fibrous healing of the tonsillar bed or fibrous ankylosis of the TMJ.
Adolescent↗
Skin cancer screening and surveillance.
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Humans↗
Vitamin D and systemic cancer: is this relevant to malignant melanoma?
1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1 alpha-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-beta and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-alpha or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH)2D3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH)2D3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin D3 in MM, but ultraviolet radiation, which is a principal source of vitamin D3, is mutagenic. Further work is necessary on the influence of serum vitamin D3 levels on the occurrence and prognosis of MM, the effects of sun protection measures on serum vitamin D3 levels in temperate climates and epidemiological studies on geographical factors and skin type on the prognosis of MM. Meanwhile, it would seem mandatory to ensure an adequate vitamin D3 status if sun exposure were seriously curtailed, certainly in relation to carcinoma of breast, prostate and colon and probably also MM.
Breast Neoplasms↗
Loss of beta-catenin expression is associated with disease progression in malignant melanoma.
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Cytoskeletal Proteins↗
The importance of accurate dosage of topical agents: a method of estimating involved area and application to calcipotriol treatment failures.
Little attention is given to accurate dosage of topical medication which is a potential source of side-effects and treatment failure. There are studies on the dosage for 'sparing' application relevant to topical steroids but not for 'liberal' application. Though calcipotriol is a first line topical treatment for psoriasis, approximately one-third of patients do not respond adequately. The aims of the present study were to define liberal dosage, to develop a method of calculation of area of involved skin and to evaluate the efficacy of calcipotriol in optimized liberal dosages, based on preliminary studies, in calcipotriol treatment failures. Weight/unit area of ointment and cream base, constituting liberal application, was determined in six normal volunteers. The area of psoriatic involvement in 24 calcipotriol non-responders was estimated by a 'fill-up' method and a modified 'hand' method. The results of the two methods were similar (Pearson correlation coefficient 0.68, P < 0.0001) but the 'hand' method proved easier in use and was the preferred method for the rest of the study. The patients applied calcipotriol at their accustomed rates for at least 2 weeks and then at the calculated liberal rates, using cream in the morning and ointment at night, for 4 weeks. The efficacy measures were Psoriasis Area and Severity Index (PASI) (primary measure), a four-point efficacy score and a visual analogue scale. As a result of the preliminary study and the actual amounts used by the patients in the psoriasis treatment study reported below, liberal application has been defined as 50 g/m2 per application for ointment base and 40 g/m2 per application for cream. At this dosage, an average individual would use approximately 100 g of medication/week to treat 10% of the body surface. During the 4-week treatment study, the psoriasis patients used an average of 39 g (SD 17 g)/m2 per application of cream and 52 g (SD 13 g)/m2 per application of ointment. All efficacy measures showed marked improvement (P < 0.0001). The frequency distribution of the PASI reduction defined responsive (70% of patients) and poorly responsive groups (30%), with mean PASI reduction of 60% and 17%, respectively.
Administration, Topical↗
A follow-up study to investigate the efficacy of initial treatment of lentigo maligna with surgical excision.
Recurrence rates following conventional surgery for lentigo maligna (LM) are reported to be between 7% and 15%. However, the studies are few, contain small numbers of patients and have relatively short follow-up. The principle aim of this study was to determine the efficacy of conventional surgery for LM in a large unbiased sample of all LM presenting in a defined geographical area. All LM cases occurring in Leicestershire between 1987 and 1996 were identified. Data were gathered from case notes, general practitioners and the Office for National Statistics (for any mortality data) and patients were invited to attend for examination. There were 89 evaluable patients treated with primary excision, representing the largest reported series to date. There was a false positive rate for diagnostic biopsy for LM (when the correct diagnosis was lentigo maligna melanoma, LMM) of 5% (95% confidence interval, CI: 1% to 14%). The initial excision was histologically incomplete in 9% (4% to 17%) of cases. In completely excised lesions (n=81) the observed recurrence rate was 20% (CI: 12% to 30%) at a mean follow-up of 42 months, which is similar to previous reports. However, Kaplan-Meier analysis yielded an estimated probability of recurrence of 31% (CI: 19% to 50%); time to relapse was up to 66 months. The age and sex of the patient and the site of the lesion were not associated with outcome, but, surprisingly, smaller lesions were associated with incomplete excision and recurrence. Fifteen current lesions were excised with similar success rates: the incomplete re-excision rate was 7% (CI: 0.2% to 32%) and the recurrence rate was 31% (CI: 12% to 83%) at 28 months. The estimated rate of transformation to LMM after initial surgical treatment was 1.5% (CI: 0.3% to 8%), and LMM was not the cause of death in any patient. These recurrence rates following complete primary excision and re-excision following recurrence were high compared with general expectations, which is largely the result of the method of analysis and the long follow-up. The high rate calls into question the accuracy of the routine histological assessment of clearance. The development of LMM was rare following surgery.
Adult↗
Clinical correlates of Breslow thickness of malignant melanoma.
BACKGROUND: Breslow thickness is a major predictor of prognosis in cutaneous malignant melanoma (MM) and patients continue to present with thick lesions, which have a poorer prognosis. OBJECTIVES: To investigate correlations of Breslow thickness with demographic variables, tumour site, clinical features, false negative diagnostic rate and clinic of primary referral. METHODS: Data were obtained from the records of 738 patients with histologically diagnosed cutaneous MM. Tumours included were in situ and invasive MM and lentigo maligna melanoma. In view of the skewed distribution of MM thickness, categories of MM thickness were used for analysis, using the commonly applied cut-offs of 0.75, 1.5 and 3.5 mm. The variables investigated were particularly associated with changes in the proportion of the thickest group, 'thick' MMs. The proportion of this thickness category is proposed as an appropriate and sensitive variable for the investigation of correlations with MM thickness. Thickness >/= 1.5 mm has also been considered in view of its prognostic significance. RESULTS: Results were similar for the two thickness groups, but more significant for the thick group. The previously described correlations of tumour thickness and increasing age (P < 0.00001) and location on head and neck (P = 0.0002), together with the independence of these variables, have been confirmed. The correlation with male gender was also confirmed but this was weak (P = 0.05). Novel findings were correlations of Breslow thickness with all features of the seven-point checklist (P varying from P = 0.01 to P < 0.00001) and tumour elevation (P < 0.00001). In general in the seven-point checklist, the absence of the major features (except variation in size) (P < 0.00001) and presence of minor features (except altered sensation) (P varying from P = 0.004 to P < 0.00001) were strongly associated with thick MMs. These results for tumour thickness are a further argument for retention of the minor features of the seven-point checklist. False negative diagnosis was found to be correlated with tumour thickness (P < 0.02) but this relationship was lost on multivariate analysis with inclusion of the clinical features. MM thickness was highly correlated with primary referral clinic (P < 0.00001). Only approximately 8% of MMs presenting to the Pigmented Lesion Clinic (PLC) were thick, while the proportion presenting to general dermatology was about three times greater and to plastic surgery about five times greater. This was maintained on multivariate analysis, including all other variables and, therefore, there must be other determining factors of referral not examined in the study. Conclusion MM thickness is associated with increasing age, male gender, location on the head and neck, all features of the seven-point checklist, tumour elevation and referral to the PLC. It is important to investigate further the reasons for general practitioner referral of different thickness MM to different types of clinic, as referral to clinics other than the PLC results in delay in the first hospital appointment, and it is now apparent that thicker lesions are disproportionately affected.
Age Factors↗
Uvulopalatopharyngoplasty versus laser assisted uvulopalatoplasty for the treatment of snoring: an objective randomised clinical trial.
This study was designed to evaluate objectively the clinical effectiveness of surgery for snoring and to compare the results of conventional uvulopalatopharyngoplasty (UPPP) and laser assisted uvulopalatoplasty (LAUP) in the treatment of snoring. Patients who had been referred for investigation and treatment of their snoring were randomly allocated to receive either UPPP or LAUP. Forty-seven patients with confirmed palatal flutter had surgery and all of them had a preoperative and postoperative objective assessment of their snoring loudness and duration in the home. The recording device (Snore Box) is simple for the patient to operate, portable with a built in microphone, and able to produce objective results, which can be automatically analysed. Of the 38 patients, who had technically valid recordings, 22 underwent LAUP and 16 UPPP. Overall the mean postoperative Snore Index (SI) was less than the preoperative SI (P < 0.0001), the average difference being 78.2 snores/h. There was no significant difference between the LAUP and UPPP regarding the fall in the SI. This study is the first objective comparative study to demonstrate the effectiveness of snoring surgery.
Adult↗
Changes in snoring during natural sleep identified by acoustic crest factor analysis at different times of night.
Sleep nasendoscopy can be used to identify the site of snoring but questions remain about how well a short assessment during drug-induced sleep reflects the natural condition. To investigate the uniformity of snoring during natural sleep we studied five patients (three men, two women) referred by their GPs for treatment of their snoring. A digital audio tape recorder captured the free-field snore sound at different times of night in hospital. Acoustic Crest Factor values were calculated on the 15 recordings made, having previously demonstrated that high crest factor values distinguish palatal from non-palatal snoring at sleep nasendoscopy. Some recordings showed reproducibility, but others showed substantial changes between recordings an hour apart. We infer that the snoring mechanism may change in some individuals during the night, with or without a change of snore site. We conclude a single recording, as in sleep nasendoscopy, may not be representative.
Acoustics↗
Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma.
Calcitriol [1,25(OH)2D3], the hormonal derivative of vitamin D3, is an antiproliferative and prodifferentiation factor for several cell types, including cultured melanocytes and malignant melanoma (MM) cells. Several polymorphisms of the vitamin D receptor (VDR) gene have been described including a FokI RFLP in exon 2, BsmI, and ApaI polymorphisms in intron 8 and an adjacent TaqI RFLP in exon 9. Alterations in vitamin D/1,25(OH)2D3 levels and polymorphisms of the VDR have been shown to be associated with several systemic malignancies. We hypothesize that polymorphism in this gene may be associated with altered susceptibility and outcome in patients with MM. A hospital-based case-control study, using 316 MM cases and 108 controls, was used to assess associations with MM susceptibility. Breslow thickness, the most important single prognostic factor in MM, was used as the outcome measure. Polymorphisms at the FokI and TaqI restriction sites were determined using PCR-based methods. Polymorphism at the FokI, but not TaqI, RFLP was associated with an altered risk of MM (P = 0.014). More importantly, variant alleles were associated with increased Breslow thickness. Thus, homozygosity for variant alleles at both RFLP (ttff genotype combination) was significantly associated with thicker tumors. (> or = 3.5 mm; P = 0.001; odds ratio = 31.5). Thus, polymorphisms of the VDR gene, which would be expected to result in impaired function, are associated with susceptibility and prognosis in MM. These data suggest that 1,25(OH)2D3, the ligand of the VDR, may have a protective influence in MM, as has been proposed for other malignancies.
Case-Control Studies↗