People with Type Diabetes Mellitus (T1DM) self-reported views on their own condition management reveal links to potentially improved outcomes and potential areas for service improvement.

BACKGROUND: The self-management of type 1 diabetes (T1DM) has moved forward in many areas over the last 40 years. Our study asked people with T1DM what is their experience of blood glucose (BG) monitoring day to day and how this influences decisions about insulin dosing. METHODS: An on-line self-reported questionnaire containing 44 questions prepared after consultation with clinicians and patients was circulated to people with T1DM 116 responders provided completed responses. Fixed responses were allocated specific values (e.g. not confident = 0 fairly confident = 1). Multivariate regression analysis was carried out. Only those 5 factors with p-value <0.05 were retained. RESULTS: 59% of respondents were >50 years old and 66% had diabetes for >20 years, with 63% of patients reporting HbA1c results ≤8% or 64 mmol/mol. Findings included; 75% used only 1 m; 56% had used the same meter for ≥3 years; 10% had tried flash monitors; 47% were concerned about current BG level; 85% were concerned about long-term impact of higher BG. 72% of respondents keep BG level high to avoid hypoglycaemia; 25% used ≥7 mmol/L as pre-meal BG target to calculate dose; 65% were concerned they might be over/under-dosing; 83% did not discuss accuracy when choosing meter. However 85% were confident in their meter's performance. The factors that linked to LOWER HbA1c included LESS units of basal insulin (p < 0.001), HIGHER number of daily BG tests (p = 0.008), LOWER bedtime blood glucose (p = 0.009), HIGHER patient's concern over long-term impact of high BG (BG) (p < 0.009 but LOWER patient's concern over current BG values (p = 0.009). The final statistical model could explain 41% of the observed variation in HbA1c. CONCLUSION: Many people still run their BG high to avoid hypoglycaemia. Concern about the longer-term consequences of suboptimal glycaemic control was associated with a lower HbA1c and is an area to explore in the future when considering how to help people with T1DM.

The association of sex hormone-binding globulin with mortality is mediated by age and testosterone in men with type 2 diabetes.

BACKGROUND: Serum sex hormone-binding globulin levels have been associated with mortality in adult men with type 2 diabetes (T2DM). OBJECTIVES: To confirm the association of serum sex hormone-binding globulin with mortality and then determine whether this association is mediated by age and total testosterone concentration. MATERIALS AND METHODS: We studied 364 men (median age: 66 years) with T2DM over a median follow-up of 4.3 years using the Cox regression to study associations between sex hormone-binding globulin, age, total testosterone, and mortality. RESULTS: Mortality was significantly and independently associated with sex hormone-binding globulin, age, and total testosterone. In pairwise combinations of age and sex hormone-binding globulin dichotomized by median values, the association of sex hormone-binding globulin with mortality was age-dependent. Relative to the combination of age >66 years/SHBG >35 nmol/L (mortality 22.5%), the other combinations were associated with significantly less mortality (mortality in men ≤66 years/SHBG ≤ 35 nmol/L was 3.23%). In men >66 years, SHBG ≤ 35 nmol/L was associated with decreased mortality (HR: 0.41, p = 0.037) compared with SHBG > 35 nmol/L. In men ≤66 years, there was no significant difference between those with sex hormone-binding globulin above or below the median (HR: 1.73, p = 0.56, reference: SHBG ≤ 35 nmol/L). TT < 12 nmol/L was associated with increased mortality in both age categories. Men >66 years with the reference combination of SHBG > 35 nmol/L and TT < 12 nmol/L (36.84%) nmol/L had significantly higher mortality than those with SHBG > 35 nmol/L and TT ≥ 12 (18.06%) and those with SHBG ≤ 35 nmol/L and TT < 12 nmol/L (13.79%). DISCUSSION: Our data suggest sex hormone-binding globulin and total testosterone have particular impact on mortality in men aged over 66 years. Further, in older men, the combination of high sex hormone-binding globulin levels and low total testosterone is associated with greater risk than either high sex hormone-binding globulin or low total testosterone individually. CONCLUSIONS: Our findings are compatible with data suggesting the importance of sex hormone-binding globulin lies in mediating free testosterone levels.

Measuring vitamin D levels: surrogates are insufficient.

AIMS: With the increasing evidence of adverse consequences because of low vitamin D levels on health demand for vitamin D, screening is increasing. The objective of the study was to assess whether parathyroid hormone (PTH) levels/bone profile is sufficient to identify patients with vitamin D insufficiency or deficiency, or whether vitamin D should be measured directly. METHODOLOGY: A total of 1560 serum specimens, with requests for 25-hydroxyvitamin D (25-OH vitamin D), calcium, phosphate, alkaline phosphatase (ALP), creatinine and PTH on the same sample were analysed at Salford Royal Hospital from November 2010 to November 2012. RESULTS: The prevalence of total vitamin D insufficiency or deficiency (defined as total 25-OH vitamin D < 50 nmol/l) was 62.9% (981/1560) overall, with males having higher proportions (67.2 vs. 59.3 per cent; χ(2) = 8.78, p = 0.003). There was no overall trend in mean serum adjusted calcium across categories of 25-OH vitamin D status but mean serum phosphate was significantly lower (F = 6.53, p < 0.0001) in patients with a 25-OH vitamin D level < 50 nmol/l. However in patients with vitamin D deficiency, a significant proportion had PTH, calcium, phosphate and alkaline phosphatase levels within the laboratory normal range. Even at a 25-OH vitamin D < 10 nmol/l, 71.6% had a normal PTH, 89.8% had normal serum calcium levels, 84.9% had normal phosphate levels and 81.6% had normal serum ALP. CONCLUSIONS: Therefore, despite the costs associated with the measurement of vitamin D, our findings show that no surrogate is adequate for screening for vitamin D deficiency.

Predicting dysglycaemia in patients under investigation for acute coronary syndrome.

AIMS: To examine methods for the identification of previously undetected dysglycaemia [diabetes and impaired glucose tolerance (IGT)] in patients investigated for possible acute coronary syndrome. Specifically, we wished to examine whether the recently advocated use of glycosylated haemoglobin (HbA1c) would enhance detection rates for diabetes in these patients. METHODS: Patients (n = 200) investigated for possible acute coronary syndrome and not previously known to have diabetes were recruited and anthropometric data collected. Random plasma glucose concentrations followed by oral glucose tolerance tests, HbA1c, fasting lipids, high sensitivity C-reactive protein and homeostatic modular assessment-insulin resistance were obtained during admission. Following discharge, the fasting plasma glucose (FPG) was repeated to determine the importance of sequential fasting levels. The accuracy of individual tests, combinations and sequential testing was assessed using receiver operating characteristic curves. A predictive index (PI) was generated using stepwise logistic regression models. RESULTS: The prevalence of diabetes and IGT were 21 and 32%, respectively. FPG >6.0 mmol/l and HbA1c ≥ 6.0% had specificities of 94.9% and 93.6% but sensitivities of only 31.7 and 39.0%, respectively. Combination and sequential testing provided little additional benefit. Use of a PI comprising FPG, HbA1c and age provided the best overall performance (75.6% sensitivity, 77.1% specificity, negative predictive value 92.4%). CONCLUSION: Our data confirm the high prevalence of dysglycaemia in this cohort. The commonly advocated screening tools have significant limitations if used in isolation, combination or sequentially. Our approach using a PI offers improved performance partly as it uses continuous data rather than arbitrary cut-off values.

The rise and fall of C-reactive protein: managing demand within clinical biochemistry.

BACKGROUND: Managing workload within the laboratory has become a key role for clinical biochemists. National benchmarking data highlighted a 31% increase in C-reactive protein (CRP) requests between 2003-2004 and 2004-2005 for the University Hospital of North Staffordshire (UHNS). The aim of this study was to examine CRP requesting patterns within the acute admissions units. METHODS: Current requesting patterns within the Accident and Emergency Department (A&E) and Medical Admissions Unit (MAU) were audited. Following discussion with clinical colleagues, the laboratory implemented agreed disease-related protocols and consultant only requesting. The impact these demand management strategies had on requesting within these units was then assessed. RESULTS: The initial data (January-June 2005) showed that the average number of requests for CRP was 918 per month from A&E and 545 per month for MAU. Implementation of demand-management strategies resulted in an overall reduction of 85% in the numbers of requests, saving the Trust approximately pound10,000 per annum. Further to the initial protocols, an IT-based logic rule was also developed to reduce CRP requests made within a 24 h time window of an initial request and educate users. CONCLUSION: This study has demonstrated that strategies to control demand at the requesting stage have been able to reduce the number of requests from acute admission units. This study forms the basis for ongoing work on inappropriate requesting and illustrates that the introduction of agreed protocols in acute settings can be used as a demand-management tool.

Epigenetic control of fetal gene expression.

Each differentiated cell type has its own epigenetic signature, which reflects its genotype, developmental history, and environmental influences, and is ultimately reflected in the phenotype of the cell and organism. Some cells undergo major epigenetic 'reprogramming' during fetal development. The proper, or improper, handling of these highly sensitive periods may have significant short-term and long-term effects on the newborn and his/her progeny. This review highlights the impact of environmental and nutritional factors on the epigenome and the potential effect of epigenetic dysregulation on maternal and fetal pregnancy outcomes, as well as possible long-term implications.

Studies of associations between disability in multiple sclerosis, skin type, gender and ultraviolet radiation.

Recent studies suggest ultraviolet radiation (UVR)/vitamin D is protective against the development of multiple sclerosis (MS). We determined if outcome in MS is associated with the surrogate for host pigmentation, skin type, and parameters of UVR exposure. We used a validated questionnaire to determine skin type and UVR exposure during childhood (0-16 years), and early adult life (17-40 years), in 448 Caucasians with MS. Outcome was assessed using the Kurtzke Expanded Disability Status Score (EDSS) and Multiple Sclerosis Severity Scale (MSSS). We studied the association of skin type and exposure with dichotomized values of EDSS (< and >or=6) and MSSS (continuous variable) using logistic and linear regression analyses, respectively. Sex, onset age and MS duration were significantly associated with outcome in all patients. In 169 females with established disease (>or=10 years), sun sensitive skin types 1 and 2 were associated with reduced risk of EDSS >or=6 (odds ratio =0.50; 95% CI = 0.26-0.97), and higher MSSS values (coefficient = -0.86; 95% CI = -1.67 to -0.05). Parameters of UVR exposure were not significantly associated with outcome. These preliminary data show an association between skin type and disability in female MS patients. They are compatible with independent studies suggesting that exposure mediates MS pathogenesis via vitamin D. Further studies are required to properly assess these potentially important findings.

Genetics and risk factors for basal cell carcinoma.

Nonmelanoma skin cancer (NMSC) is the commonest cancer in whites and its incidence is increasing worldwide. The prevalence of this cancer is predicted to equal that of all others combined and it was estimated that there were over 2 million cases diagnosed in the U.S.A. in 2004. Patients exhibit marked differences in clinical phenotype with variations in tumour numbers, rate of tumour accrual, site and histological subtype. Furthermore, patients are at increased risk of other cutaneous and noncutaneous cancers. The factors accounting for this variation are complex and still not completely understood. Clearly, ultraviolet light (UV) exposure is a major influence but its relationship to clinical phenotype is not yet clear. In addition, immunosuppression is a significant risk factor. Our group has identified high-risk groups for the development of further basal cell carcinoma (BCC), namely patients with truncal BCC and those presenting with tumour clusters. This presentation will concentrate on these clinical subgroups as well as immunosuppressed patients. These groups represent significant management challenges and are areas where novel, nonsurgical treatment options may make a significant clinical impact in patient care. The risk factors predisposing to these clinical phenotypes will be discussed, including genetic factors and UV exposure. Potential clinical applications, including predictive indices, will be considered.

Asthma severity and atopy: how clear is the relationship?

BACKGROUND: The relationship between asthma severity and atopy is complex. Many studies have failed to show significant relationships between clinical severity or lung function and markers of atopic sensitisation. AIM: To determine whether increasing asthma severity is related to atopic sensitisation in a population of children with asthma. METHODS: A total of 400 children (7-18 years) with asthma were recruited as part of a multicentre study of the genetics of asthma. Detailed phenotypic data were collected on all participants. Associations between measures of asthma severity and atopic sensitisation were sought using multilevel models allowing variation at the individual and family level. RESULTS: Children recruited to the study had a range of asthma severities, with just over a third having mild persistent asthma. The logarithm of total serum IgE was associated with increased asthma severity score, decreased FEV1, increased airways obstruction, risk of hospital admission, and inhaled steroid use. Increasing skin prick test reactivity to a panel of seven aeroallergens was associated with increased risk of hospital admission, use of an inhaled steroid, and airways obstruction. The results remained highly significant after corrections for age, gender, and birth order. CONCLUSIONS: In children with asthma, increasing atopy is associated with increasing asthma severity. However, the relationships between asthma severity and skin prick tests, and asthma severity and total serum IgE values, appear subtly different.

Novel polymorphism in the promoter region of the human nerve growth-factor gene.

We describe a novel T to C transition at position -198 from the transcription start of the human nerve growth-factor (NGF) gene. In British Caucasoid healthy control group that we have genotyped, T and C allele frequencies are 0.633 and 0.367, respectively. This polymorphism affects vitamin D receptor (VDR) binding to its motif in the NGF promoter.

Effects of glutathione S-transferase M1, T1 and P1 on lung function in asthmatic families.

RATIONALE: Previous data have suggested that glutathione-S-transferase (GST) genotypes are important in determining the rate of lung function growth in childhood. This effect was most marked in Caucasian children with asthma. OBJECTIVES: We investigated the association of lung function with GSTM1, GSTP1 and GSTT1 genotypes in Caucasian families with asthma. METHODS: Four hundred and eighteen children and 316 parents from 224 Caucasian families were recruited via a child with asthma, the proband. Associations between lung function and GST genotype were determined using multilevel models. RESULTS: There were no observed associations between lung function and GST genotype in parents. However, in the children, the GSTP1 val(105)/val(105) and GSTM1 null genotypes were associated with significantly higher forced expiratory volume in 1 s (FEV(1)) and FVC values as percentage of predicted. This effect was not statistically significant in the probands but was marked in their siblings in whom GSTP1 val(105)/val(105) was associated with 9.4% higher FEV(1) and 10.7% higher FVC (P=0.005 and 0.001, respectively). The GSTM1 null genotype was associated with a 6.7% higher FEV(1) and 4.1% higher FVC (P=0.003 and 0.063, respectively). These effects remained significant after correcting for the confounders of individual atopic status, tobacco smoke exposure and familial aggregation of lung function values. CONCLUSIONS: GSTM1 and GSTP1 genotypes are important determinants of lung function in childhood. The smaller differences seen in probands are predicted by a simple model in which more rapid decline in lung function is seen in these individuals.

Glutathione S-transferase T1 polymorphisms are associated with outcome in colorectal cancer.

Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22-2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (<70 versus > or =70 years at diagnosis), in the patients diagnosed <70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31-0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12-3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.

Regional variation of airway hyperresponsiveness in children with asthma.

Families with asthmatic children were recruited to take part in a multi-centre collaborative study into the genetics of asthma. Detailed phenotypic information was collected on all family members including: lung function, anthropomorphic measurements, response to methacholine challenge, skin prick testing, serum IgE measurements and a detailed nurse-administered questionnaire. Families were eligible for entry into the study if they had two children with a doctor-diagnosis of asthma. Bennett/Twin nebulisers were supplied to each centre from a single source and these were calibrated to determine gravimetric nebuliser output prior to use. Asthmatic probands from each centre had similar degrees of asthma severity and atopy. There was no significant difference in the sex ratios or ages of the probands or numbers of parents with a history of smoking in the families recruited at each centre. However, there was a significant difference in the number of children with airway hyperresponsiveness, with 90% of the North Staffordshire group but only 60% of the Sheffield group having a PC20 of <8 mg/ml for methacholine. This difference highlights the difficulty of using families from different centres in genetic and epidemiological studies.

Maternal glutathione S-transferase GSTP1 genotype is a specific predictor of phenotype in children with asthma.

Maternal factors are known to influence the heritability and expression of asthma and atopy. We report the association of maternal, paternal and proband GSTP1 genotype with lung function in 145 Caucasian children with asthma. GSTP1 Val105/Val105 and Ala114/Val114 genotypes in the child were associated with non-significant increases in lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and the FEV1/FVC ratio). Paternal genotype had no influence on lung function in the child. In contrast, maternal GSTP1 Val105/Val105 genotype was significantly associated with offspring lung function and was strongly predictive of FEV1/FVC (Val105/Val105 105.2%, Ile105/Val105 and Ile105/Ile105 97.9% p=0.006) and maternal GSTP1 Ala114/Val114 genotype was associated with significantly higher FEV1 (Ala114/Val114 109.0%, Ala114/Ala114 99.0% p=0.008), and FEV1/FVC ratios (Ala114/Val114 104.1%, Ala114/Ala114 98.2% p=0.04). The associations between maternal GSTP1 Val105/Val105 genotype and FEV1/FVC and maternal GSTP1 Ala114/Val114 genotype and FEV1 remained significant (p=0.003 and p=0.007) after correction for child and maternal atopic status, passive smoke exposure, smoking during pregnancy, individual and paternal GSTP1 genotype and was independent of transmission to the child. These data support the hypothesis that maternal GSTP1 genotype can act as a specific risk factor which has ex utero consequences for children with asthma. As a child's genotype is not independent of maternal genotype, effects seen in candidate gene studies may be due at least in part to this phenomenon.

Basal cell carcinoma: from host response and polymorphic variants to tumour suppressor genes.

The molecular factors and events that characterize susceptibility and outcome in cutaneous basal cell carcinoma (BCC) have been the focus of much research interest. As a result, we are beginning to understand the complex relationships between exposure to ultraviolet radiation (UVR), host response and the resulting damage to key genes that characterize these tumours. In this review, we will focus on genetic factors that influence susceptibility and outcome. While the search for susceptibility genes has generally resulted in the identification of low penetrance allelic variants, studies on modifier genes influencing outcome variables such as tumour number, age of onset and tumour subtype have identified factors with higher potential impact. Here we will briefly describe some recent work on the genetic basis of the immune response to UVR, the effect of UVR on the generation of reactive oxygen species and their detoxification, and the role of onco- and tumour suppressor genes. Areas for further research are highlighted, together with a consideration of possible applications in clinical practice.

Susceptibility to basal cell carcinoma: associations with PTCH polymorphisms.

Loss of function of the human patched gene (PTCH) is common and critical in basal cell carcinoma (BCC) development. Indirect evidence suggests polymorphism in PTCH mediates BCC risk. We studied 659 BCC cases and 300 controls to determine if exon 2(318), 3(429), 11(1552), 12(1665), 12(1686), 14(2199) and 23(3944) and intron 9(1336-135) and 15(2560+9)PTCH variants were sufficiently common for use in case-control studies, and if selected markers were associated with risk. Intron 15(2560+9) and exon 23(3944) variants were studied further. Their genotype frequencies were not significantly different in controls and cases, though frequency of the G(2560+9)-C(3944) haplotype was lower in all cases (odds ratio=0.44, p=0.009) and those stratified by BCC site and rate of development of further tumours. This association was not mediated by the extent of UVR exposure. We confirmed the robustness of these findings by showing these associations demonstrated similar odds ratios in two groups of randomly selected cases and controls, and using the false positive report probability (FPRP) approach described by Wacholder et al. (2004). The FPRP value (0.168) was in the noteworthy category. These data, showing for the first time that PTCH polymorphism mediates susceptibility, are compatible with reports showing that PTCH haploinsufficiency influences development of BCC precursor lesions.

The role of polymorphisms of glutathione S-transferases GSTM1, M3, P1, T1 and A1 in susceptibility to alcoholic liver disease.

AIMS AND METHODS: Oxidant stress is proposed to be an important pathogenic factor in liver damage related to alcohol. The glutathione S-transferases (GSTs) are a group of polymorphic enzymes that are important in protection against oxidant stress. As there is evidence for genetic susceptibility to alcohol-related liver disease we have compared the frequency of polymorphisms of GSTM1, M3, P1, T1 and A1 by polymerase chain reaction (PCR) on leucocyte DNA in patients from North Staffordshire, Birmingham and Liverpool with alcohol-related chronic liver disease heavy drinking and normal local controls. RESULTS: There were no significant differences in GSTM1, GSTM3 or GSTP1 genotype frequencies among patients, drinking and non-drinking controls from the three centres. There was a significant increase in the GSTT1 null Liverpool alcoholic liver disease (ALD) patients compared with corresponding non-drinking controls (26.3 and 14.6%, respectively; P = 0.044, odds ratio (OR) = 2.1, 95% CI = 1.1-4.7) though this was not repeated in the Birmingham and North Staffordshire cohorts. For GSTA1, the -69 CC genotype was associated with increased risk of ALD in the Liverpool group, but a reduced risk in the North Staffordshire group. CONCLUSIONS: We have failed to demonstrate within the limitation of a case-control study a reproducible significant association of GST polymorphisms with susceptibility to ALD but there are suggestions that GSTA1 and GSTT1 warrant further study.