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CONTEXT:Uncoupling protein 2 (UCP2) is involved in regulating ATP synthesis, generation of reactive oxygen species and glucose-stimulated insulin secretion in β-cells. Polymorphisms in UCP2 may be associated with obesity and type 2 diabetes mellitus.OBJECTIVE:To determine the influence of a functional UCP2 promoter polymorphism (−866G>A, rs659366) on obesity, type 2 diabetes and intermediary metabolic traits. Furthermore, to include these and previously published data in a meta-analysis of this variant with respect to its impact on obesity and type 2 diabetes.DESIGN:We genotyped UCP2 rs659366 in a total of 17 636 Danish individuals and established case-control studies of obese and non-obese subjects and of type 2 diabetic and glucose-tolerant subjects. Meta-analyses were made in own data set and in publicly available data sets. Quantitative traits relevant for obesity and type 2 diabetes were analysed within separate study populations.RESULTS:We found no consistent associations between the UCP2 −866G-allele and obesity or type 2 diabetes. Yet, a meta-analysis of data from 12 984 subjects showed an association with obesity (GA vs GG odds ratio (OR) (95% confidence interval (CI)): 0.894(0.826-0.968) P=0.00562, and AA vs GG OR(95% CI): 0.892(0.800-0.996), P=0.0415. Moreover, a meta-analysis for type 2 diabetes of 15 107 individuals showed no association. The −866G-allele was associated with elevated fasting serum insulin levels (P=0.002) and HOMA insulin resistance index (P=0.0007). Insulin sensitivity measured during intravenous glucose tolerance test in young Caucasian subjects (n=377) was decreased in carriers of the GG genotype (P=0.05).CONCLUSIONS:The UCP2 −866G-allele is associated with decreased insulin sensitivity in Danish subjects and is associated with obesity in a combined meta-analysis. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Genome-wide association studies have identified novel WHR and BMI susceptibility loci. The aim of this study was to elucidate if any of these loci had an effect on quantitative measures of glucose homeostasis, including estimates of insulin release and insulin sensitivity in an epidemiological setting. Methods: By applying an additive genetic model, 14 WHR-associated gene variants and 18 BMI-associated variants were investigated for their relationships with glucose-related metabolic traits in treatment-naive individuals from the population-based Inter99 study sample ( n = 6,039). Results: Of the variants associated with BMI, the QPCTL rs2287019 C allele was associated with an increased insulinogenic index of 7.4% per risk allele ( p = 4.0 × 10) and increased disposition index of 5.6% ( p = 6.4 × 10). The LRP1B rs2890652 C allele was associated with insulin resistance, showing a 3.3% increase ( p = 0.0011) using the HOMA-insulin resistance (HOMA-IR) index and a 2.2% reduction ( p = 0.0014) with the Matsuda index. Of the variants associated with WHR, LYPLAL1/SLC30A10 rs4846567 G allele carriers showed a 5.2% lower HOMA-IR ( p = 0.00086) in women, indicating improved insulin sensitivity. Female carriers of the VEGFA rs6905288 A allele were insulin resistant, with a 3.7% increase in HOMA-IR ( p = 0.00036) and 4.0% decrease in Matsuda index ( p = 2 × 10). Conclusions: Our correlative findings from analysing single-locus data suggest that some variation in validated BMI and WHR loci are associated with either increased or decreased insulin sensitivity and thereby potentially with metabolically healthy or metabolically unhealthy subsets of obesity. The results call for testing in larger study samples and for further physiological exploration of the possible metabolic implications of these loci. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The glucagon gene ( GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits. Methods: GCG was re-sequenced as a candidate gene in 865 European individuals. Twenty-nine variants were identified. Four variants that were considered to have a likelihood for altered functionality: rs4664447, rs7581952, Ile158Val and Trp169Ter, were genotyped in 17,584 Danes. Results: When examined in 5,760 treatment-naive individuals, homozygous carriers of the low frequency (minor allele frequency 2.3%) G allele of rs4664447, predicted to disrupt an essential splice enhancer binding site, had lower levels of fasting plasma glucose (mean ± SD, 4.8 ± 1.2 vs 5.5 ± 0.8 mmol/l, p = 0.004); fasting serum insulin (22 ± 14 vs 42 ± 27 pmol/l, p = 0.04); glucose-stimulated serum insulin (159 ± 83 vs 290 ± 183 pmol/l, p = 0.01) and adult height (165 ± 10 vs 172 ± 9 cm, p = 0.0009) compared with A allele carriers. During oral glucose tolerance and hyperglycaemic arginine stimulation tests, the plasma AUC for GLP-1 (730 ± 69 vs 1,334 ± 288 pmol/l × min, p = 0.0002) and basal and stimulated levels of serum insulin and plasma glucagon were ∼50% decreased ( p < 0.001) among three homozygous carriers compared with nine matched wild-type carriers. rs7581952, Ile158Val and Trp169Ter (where 'Ter' indicates 'termination') variants of GCG did not significantly associate or co-segregate with the metabolic traits examined. Conclusions/interpretation: Re-sequencing of GCG revealed a low frequency intronic variant, rs4664447, and follow-up physiological studies suggest that this variant in homozygous form may cause decreased fasting and stimulated levels of insulin, glucagon and GLP-1. Overall, our findings suggest that variation in GCG has no major impact on carbohydrate metabolism in the study populations examined. [ABSTRACT FROM AUTHOR]

ims/hypothesis: By combining multiple genome-wide association (GWA) studies and comprehensive replication efforts, 12 novel type 2 diabetes associated loci have recently been discovered. Here we evaluate the effect of lead variants of these loci on estimates of insulin release and insulin resistance derived from an oral glucose tolerance test. Methods: We examined 12 lead variants in or near HMGA2, CENTD2 (also known as ARAP1), KLF14, PRC1, TP53INP1, ZBED3, ZFAND6, CHCHD9, DUSP9, KCNQ1, BCL11A and HNF1A in 5,722 middle-aged people from the population-based Inter99 sample. Results: Carriers of the major diabetogenic allele of rs1552224 in CENTD2 had increased 30-min plasma glucose values (2.0%, p = 2 × 10) as well as 4.2% reduced insulin release 30 min after an oral glucose load ( p = 0.001). Risk allele carriers also had decreased BIGTT-acute insulin release (AIR), which is a surrogate measure of insulin release where sex, BMI, plasma glucose and serum insulin are integrated (5.3%, p = 8 × 10). In addition, a decreased corrected insulin response (CIR; 9.9%, p = 3 × 10) was observed. For rs5945326 near DUSP9 on the X-chromosome we stratified according to sex. Male carriers of the risk allele showed nominally decreased BIGTT-AIR (2.6%, p = 0.01). No associations with intermediate metabolic traits were found in women. For the remaining ten lead variants no consistent associations were demonstrated. Conclusions/interpretation: Of the lead variants from 12 novel type 2 diabetes associated loci, CENTD2 significantly associated with increased plasma glucose values and decreased glucose-stimulated insulin release, suggesting that the diabetogenic effect of this locus is mediated through an impaired pancreatic beta cell function. [ABSTRACT FROM AUTHOR]

ims/hypothesis: A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/ C2CD4A/ C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/ C2CD4A/ C2CD4B rs7172432 variant and diabetes-related intermediary traits. Methods: We genotyped the rs7172432 variant in the population-based Inter99 cohort ( n = 6,784) and analysed quantitative diabetes-related traits in 5,722 non-diabetic participants who all were examined by an OGTT. Results: The diabetes-associated A allele was associated with 0.60 cm higher waist circumference ( p = 0.004), 0.037 mmol/l higher fasting plasma glucose ( p = 4 × 10) and 0.11 mmol/l higher plasma glucose at 30 min during an OGTT ( p = 4 × 10). In analyses adjusted for concomitant insulin sensitivity levels the diabetogenic allele was associated with a lower acute glucose-stimulated insulin response (GSIR) as estimated by 30 min serum insulin ( β = −0.039, p = 2 × 10), insulinogenic index ( β = −0.057, p = 1 × 10) and BIGTT-acute insulin release ( β = −0.041, p = 9 × 10). As rs7172432 is situated in a region previously associated with glycaemic traits, we tested linkage disequilibrium (LD) with the reported regional lead single-nucleotide polymorphisms for fasting (rs11071657) and 2 h plasma glucose (rs17271305), and performed conditional analyses of rs7172432. Rs7172432 showed moderate LD with rs11071657 and rs17271305 ( R < 0.34) and we found strong association by almost unchanged effect sizes of rs7172432 with plasma glucose and estimates of GSIR in analyses conditional on rs11071657 and rs17271305. Conclusions/interpretation: The diabetogenic VPS13C/ C2CD4A/ C2CD4B rs7172432 A allele associates with GSIR in non-diabetic individuals from the general population, suggesting an impaired beta cell function as an intermediary diabetes-related trait. [ABSTRACT FROM AUTHOR]

ims: Increased glucose excursions and postprandial hyperglycaemia have been suggested as unique risk factors for cardiovascular disease (CVD) and mortality in patients with diabetes mellitus. Much of the evidence is based on a single 2 h glucose value after oral glucose tolerance testing in epidemiological studies. We examined the association between various indices of glycaemia measured during everyday activities and metabolic CVD risk factors in the A1C-Derived Average Glucose (ADAG) study. Methods: Participants (268 with type 1 diabetes, 159 with type 2 diabetes) completed 16 weeks of intensive continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG). From these data, common indices of postprandial glycaemia, overall hyperglycaemia, glucose variability and HbA were derived. The associations between glycaemic indices and known CVD risk factors (lipids, high-sensitivity C-reactive protein and blood pressure) were explored in linear regression models. Results: For both diabetes types, the overall strongest associations with CVD risk factors were seen for the measures of average glycaemia (mean blood glucose and HbA). Associations between self-monitored postprandial and fasting glucose and CVD risk factors were weaker, but significant. Measurements of blood glucose variability showed non-significant associations. Overall, calculations based on CGM were not more informative than those based on frequent SMBG. Conclusions/interpretation: Mean glycaemia and HbA show consistent and stronger associations with CVD risk factors than fasting glucose or postprandial glucose levels or measures of glucose variability in patients with diabetes. [ABSTRACT FROM AUTHOR]

ims/hypothesis: We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237). Methods: Information about size at birth and prematurity was identified from original midwife records in 4,744 middle-aged Danes. Type 2 diabetes status, insulin sensitivity (Matsuda index) and beta cell function (disposition index) were assessed using a 75 g oral glucose tolerance test. Participants born prematurely were compared with a group of at-term participants born small for gestational age. Results: An increase in birthweight of 1 kg was associated with a 51% (OR 0.49, 95% CI 0.35-0.69) reduced risk of type 2 diabetes. Ponderal index, reflecting thinness at birth, was associated with type 2 diabetes to the same extent as birthweight. The prevalence of type 2 diabetes was increased to a similar degree in participants born prematurely and participants born small for gestational age, although the former had a higher ponderal index at birth. In addition, birthweight z-scores, reflecting fetal growth rate, were unrelated to the risk of type 2 diabetes and to other measures of glucose regulation in participants born prematurely. While low birthweight was inversely associated with insulin sensitivity and beta cell function, prematurity was associated solely with decreased insulin sensitivity. Conclusions/interpretation: While the association between birthweight and risk of type 2 diabetes is mediated via combined effects on beta cell function and insulin sensitivity, prematurity seems to influence risk of type 2 diabetes via attenuated insulin sensitivity only and independently of fetal growth rates. [ABSTRACT FROM AUTHOR]

The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. Midwife records from the Danish State Archives provided information on mother’s age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 ( β = −33 g [95% CI −55, −10], p = 0.004) and CDKAL1 rs7756992 ( β = −22 g [95% CI −43, −1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis ( n = 24,885) ( β = −20 g [95% CI −29, −11], p = 5 × 10−6). The HHEX-IDE rs1111875 variant showed no significant association among Danes ( p = 0.09); however, in a meta-analysis ( n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight ( β = −16 g [95% CI −24, −8], p = 8 × 10−5). On average, individuals with high genetic risk (≥25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) ( β = −35 g [95% CI −69, −2], p = 0.037). We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles. [ABSTRACT FROM AUTHOR]

Real-life glycaemic profiles of healthy individuals are poorly studied. Our aim was to analyse to what extent individuals without diabetes exceed OGTT thresholds for impaired glucose tolerance (IGT) and diabetes. In the A1C-Derived Average Glucose (ADAG) study, 80 participants without diabetes completed an intensive glucose monitoring period of 12 weeks. From these data, we calculated the average 24 h glucose exposure as time spent above different plasma glucose thresholds. We also derived indices of postprandial glucose levels, glucose variability and HbA1c. We found that 93% of participants reached glucose concentrations above the IGT threshold of 7.8 mmol/l and spent a median of 26 min/day above this level during continuous glucose monitoring. Eight individuals (10%) spent more than 2 h in the IGT range. They had higher HbA1c, fasting plasma glucose (FPG), age and BMI than those who did not. Seven participants (9%) reached glucose concentrations above 11.1 mmol/l during monitoring. Even though the non-diabetic individuals monitored in the ADAG study were selected on the basis of a very low level of baseline FPG, 10% of these spent a considerable amount of time at glucose levels considered to be ‘prediabetic’ or indicating IGT. This highlights the fact that exposure to moderately elevated glucose levels remains under-appreciated when individuals are classified on the basis of isolated glucose measurements. [ABSTRACT FROM AUTHOR]

Diabet. Med. 27, 906–910 (2010) Aims Glycated haemoglobin (HbA1c) has been proposed as an alternative to the oral glucose tolerance test for diagnosing diabetes. We compared the cardiovascular risk profile of individuals identified by these two alternative methods. Methods We assessed the prevalence of cardiovascular risk factors in individuals with undiagnosed diabetes according to the World Health Organization classification or by the newly proposed HbA1c level ≥ 6.5% among 6258 participants of the Danish Inter99 study. Receiver operating curve analysis assessed the ability of fasting: 2-h plasma glucose and HbA1c to distinguish between individuals at high and low risk of ischemic heart disease, predicted by the PRECARD program. Results Prevalence of undiagnosed diabetes was 4.1% [95% confidence interval (CI) 3.7–4.7%] by the current oral glucose tolerance test definition, whereas 6.6% (95% CI 6.0–7.2%) had diabetes by HbA1c levels. HbA1c-defined individuals were relatively older with higher proportions of men, smokers, lipid abnormalities and macro-albuminuria, but they were leaner and had lower blood pressure. HbA1c was better than fasting- and 2-h plasma glucose at distinguishing between individuals of high and low predicted risk of ischaemic heart disease; however, the difference between HbA1c and fasting- and 2-h plasma glucose was not statistically significant. Conclusions Compared with the current oral glucose tolerance test definition, more individuals were classified as having diabetes based on the HbA1c criteria. This group had as unfavourable a risk profile as those identified by the oral glucose tolerance test. [ABSTRACT FROM AUTHOR]

We aimed to examine whether sex differences in fasting plasma glucose (FPG), 2 h post-OGTT plasma glucose (2hPG) and HbA1c could be explained by differences in body size and/or body composition between men and women in a general non-diabetic Danish population. Moreover, we aimed to study to what degree the newly suggested high-risk HbA1c criteria overlapped with the current OGTT-based criteria of glucose intolerance. We used cross-sectional data from 6,006 non-diabetic men and women. HbA1c and FPG levels were measured and a 75 g OGTT was performed in all individuals. Height, weight and waist and hip circumferences were measured and BMI was calculated. Data were analysed in age-adjusted linear regression models. Men had higher FPG and HbA1c levels than women, and women had higher 2hPG levels than men. Sex differences in 2hPG levels were explained by differences in height and FPG levels, but sex differences in FPG or HbA1c levels were not explained by anthropometric measures. Among individuals with HbA1c in the high-risk range (6.0–6.5%), 73% had normal glucose tolerance. Sex differences in 2hPG levels after an OGTT may to some extent be a consequence of giving the same amount of glucose to individuals with different body size. In contrast, sex differences in FPG and HbA1c levels are likely to have a true physiological basis. In clinical practice, the HbA1c assay may be more convenient than the OGTT, but it is important to note that different populations are identified by the two methods. ClinicalTrials.gov NCT00289237 Supported by grants from the Danish Diabetes Association, the Danish Medical Research Council, the Danish Centre for Evaluation and Health Technology Assessment, Novo Nordisk, GlaxoSmithKline, Copenhagen County, The Danish Heart Foundation, The Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, and the Becket Foundation. [ABSTRACT FROM AUTHOR]

Diabet. Med. 27, 550–555 (2010) Aims British guidelines on vascular disease prevention recommend adding a random (casual) blood glucose measurement to a lipid profile in those aged ≥ 40 years. To assess this recommendation, we compared the predictive value of a risk model based on the Framingham risk score alone to one which additionally included information on fasting blood glucose, with respect to incident coronary heart disease (CHD) over 11 years. Method Men and women aged 40–63 years in Whitehall II were followed up for incident CHD: death/non-fatal myocardial infarction; angina confirmed by doctor diagnosis or electrocardiogram (ECG) and all first events. Fasting blood glucose was specified as a continuous variable or categorized by World Health Organization (WHO) 1999 glycaemic status (normal glucose tolerance, impaired fasting glucose or newly diagnosed diabetes). Results The hazard ratio for incident CHD was 1.10 (95%CI 1.09; 1.12) in men and 1.13 (1.10; 1.17) in women per percentage point increase in Framingham risk. The excess risk remained unchanged in models which added glycaemic status or continuous fasting glucose. The area under the receiver operating characteristic (ROC) curve for the Framingham score and incident coronary heart disease [0.70 (0.68; 0.73)] did not change when glycaemic status or fasting glucose was added to the prediction model. Reclassification with these modified models improved discrimination based on the Framingham score alone when glycaemic status was added, net reclassification improvement 2.4% (95% CI 0.2%; 4.6%), but not when fasting glucose was added. Conclusion Better detection of unrecognized diabetes is a valuable consequence of including a random blood glucose in a vascular risk profile. Our results suggest that this strategy is unlikely to improve risk stratification for CHD. [ABSTRACT FROM AUTHOR]

Diabet. Med. 27, 46–53 (2010) Aim To compare the performance of nine published strategies for the selection of individuals prior to screening for undiagnosed diabetes. Methods We conducted a validation study, based on a cross-sectional analysis of 6990 participants of the Whitehall II study, an occupational cohort of civil servants in London. We calculated sensitivity, specificity and the area under the receiver operating characteristic (ROC) curve, indicative of the ability of a risk score to correctly identify those with undiagnosed diabetes. Results The prevalence of unknown diabetes was 2.0%. At a set level of sensitivity (0.70), the specificity of the different scores ranged between 0.41 and 0.57. A reference model, based solely on age and body mass index had an area under the ROC curve of 0.67 [95% confidence interval (CI): 0.62, 0.72]. Four scores had a lower area under the ROC curve (lowest ROC AUC: 0.62; 95% CI: 0.58, 0.67) compared with the reference model, while the other five scores had similar areas (highest ROC AUC: 0.68; 95% CI: 0.63, 0.72). All ROC curve areas were lower than those reported in the original publications and validation studies. Conclusions Existing risk scores for the detection of undiagnosed diabetes perform less well in a large validation cohort compared with previous validation studies. Our study indicates that non-invasive risk scores require further refinement and testing before they can be used as the first step in a diabetes screening programme. [ABSTRACT FROM AUTHOR]

The aim of the study was to analyse how strongly commuting and leisure-time physical activity affect progression to diabetes and to study whether this relationship is different in individuals with isolated impaired fasting glucose (i-IFG) and isolated impaired glucose tolerance (i-IGT). We studied the incidence of diabetes in 4,031 individuals without diabetes at baseline who participated in the baseline and 5 year follow-up examinations of a population-based primary prevention study, the Inter99 Study. Glucose tolerance status at baseline and at follow-up were based on OGTTs. Commuting and leisure-time physical activity at baseline were assessed by questionnaire. We present rate ratios from Poisson regression analyses adjusted for relevant confounders. The progression rate to diabetes was lower among physically active individuals in the total study population and particularly among those with i-IGT. The associations were attenuated and lost statistical significance after further adjustment for BMI. We observed no impact of physical activity on the progression to diabetes in individuals with i-IFG. Physical activity was associated with a lower progression to diabetes in the total study population and in individuals with i-IGT, a condition primarily characterised by muscle insulin resistance. Physical activity did not predict progression to diabetes in individuals with i-IFG, a condition primarily characterised by hepatic insulin resistance. Our results suggest that there is a differential relationship between physical activity and progression to diabetes among those with i-IFG and i-IGT. Therefore, clinical trials testing the effect of physical activity on progression from i-IFG to diabetes are needed. ClinicalTrials.gov ID No.: NCT00289237 The Danish Medical Research Council, the Danish Center for Evaluation and Health Technology Assessment, Novo Nordisk, Copenhagen County, the Danish Heart Foundation, the Danish Diabetes Association, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation and the Becket Foundation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Limb-sparing surgery with hemipelvic megaprosthetic replacement is often limited by the high rate of associated complications. The aim of this evaluation was to assess clinical and oncological findings with respect to type, treatment and outcome of post-operative complications. Methods: First results of 40 patients treated with individual MUTARS® hemipelvic endoprostheses were evaluated in a prospective multicenter study. Results: The mean follow-up period of the 27 male and 13 female patients was 24 months (range 1–61). The diagnosis was, in 29 cases, a primary bone or soft tissue sarcoma, in 11 patients, a metastasis. Clinical evaluation showed a mean Enneking score of 50% (range 10–70%). The oncological outcome revealed 25 patients (62.5%) alive with no evidence of disease. Seventeen of them had a primary tumour, eight a metastatic malignancy. Seven patients (17.5%) had died of their disease and eight (20%) were still alive but had developed a metastases and/or had had a recurrence of the primary tumour. The one- and two-year overall survival rate of the patients was 89% (± 0.10) and 81% (± 0.19), respectively. Post-operative complications occurred in 75% of the patients, predominantly wound-related disorders. The rate of implant revision was 22.5% with three septic and six aseptic cases of implant loosening. The estimated three-year-survival rate of the implant was 61.4% [CI95%: 0.36;0.87]. Conclusions: Periacetabular endoprosthetic replacement showed an acceptable functional and oncological outcome but had a high complication rate owing, predominantly, to infection. The indication for hemipelvic prosthesis in patients with a metastatic disease must be considered seriously. [Copyright &y& Elsevier]

Objectives. The heat shock proteins 60 and 70 (HSP60, HSP70) play an important role in cytoprotection. Under stress conditions they are released into the circulation and elicit an immune response. Anti-HSP60 and anti-HSP70 antibody levels have been associated with cardiovascular disease. Type 1 diabetes is associated with a greatly increased risk of micro- and macrovascular complications. Therefore, we investigated whether anti-HSP60 and anti-HSP70 antibody levels were associated with micro- and macrovascular complications in type 1 diabetic patients. Design. A cross-sectional nested case-control study from the EURODIAB Study of 531 type 1 diabetic patients was performed. Subjects. Cases ( n = 363) were defined as those with one or more complications of diabetes; control subjects ( n = 168) were all those with no evidence of any complication. We measured anti-HSP60 and anti-HSP70 antibody levels and investigated their cross-sectional associations with diabetic complications. Results. Anti-HSP70 antibody levels were significantly greater in control than in case subjects, whereas anti-HSP60 antibody levels were similar in the two groups. In logistic regression analysis, anti-HSP70 levels in the upper quartiles were associated with a 47% reduced odds ratio of micro/macrovascular complications, independently of conventional risk factors, markers of inflammation and endothelial dysfunction [odds ratio(OR) = 0.53, 95% confidence intervals(CI): 0.28–1.02]. Conclusions. In this large cohort of type 1 diabetic subjects, we found an independent and inverse association between serum anti-HSP70 antibody levels and diabetic micro/macrovascular complications. This suggests that anti-HSP70 antibody levels may be a novel marker of protection from chronic diabetic complications. [ABSTRACT FROM AUTHOR]

Background and Purpose: The histamine H4 receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H4 receptor antagonist, A-940894 (4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine).Experimental Approach: We have analysed the pharmacological profile of A-940894 at mouse native, rat recombinant and human recombinant and native, histamine H4 receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan-induced peritonitis.Key Results: A-940894 potently binds to both human and rat histamine H4 receptors and exhibits considerably lower affinity for the human histamine H1, H2 or H3 receptors. It potently blocked histamine-evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine-induced shape change of mouse bone marrow-derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell-dependent model of zymosan-induced peritonitis, A-940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D2 levels. Finally, A-940894 has good pharmacokinetic properties, including half-life and oral bioavailability in rats and mice.Conclusions and Implications: These data suggest that A-940894 is a potent and selective histamine H4 receptor antagonist with pharmacokinetic properties suitable for long-term in vivo testing and could serve as a useful tool for the further characterization of histamine H4 receptor pharmacology. [ABSTRACT FROM AUTHOR]

Aims Screening and prevention strategies for Type 2 diabetes require insight into the aetiological and potentially different risk factors leading to early impairments of fasting plasma glucose (FPG) and 2-h post-load plasma glucose (2hPG) levels. We studied whether risk factors predicting subtle elevations of FPG levels were different from those predicting elevations of 2hPG levels in men and women. Methods We used baseline and 5-year follow-up data from middle-aged men and women with normal glucose tolerance (NGT) at baseline in the Danish population-based Inter99 study ( n = 3164). Anthropometric and non-anthropometric baseline predictors of the 5-year FPG and 2hPG levels were estimated in linear regression models stratified by gender. Results In men, but not in women, smoking and family history of diabetes predicted increased FPG levels, whereas high physical activity predicted a decline in 2hPG levels. Among the anthropometric variables, large waist circumference was the strongest predictor of increased FPG levels in men, whereas high body mass index (BMI) was the strongest predictor of increased FPG levels in women. In both men and women, BMI and waist circumference were equally strong in predicting 2hPG levels. Furthermore, short height predicted increased 2hPG levels in men, and short height and low hip circumference predicted increased 2hPG levels in women. Conclusions Risk factors that predict future FPG levels are different from those predicting future 2hPG levels. Furthermore, different risk factors predict glycaemic levels in men compared with women. These findings indicate that different aetiological pathways may lead to Type 2 diabetes in men and women. [ABSTRACT FROM AUTHOR]

Summary: Objective: Mesenchymal stem cells (MSCs) are a population of cells broadly discussed to support cartilage repair. The differentiation of MSCs into articular chondrocytes is, however, still poorly understood on the molecular level. The aim of this study was to perform an almost genome-wide screen for genes differentially expressed between cartilage and MSCs and to extract new markers useful to define chondrocyte differentiation stages. Methods: Gene expression profiles of MSCs (n =8) and articular cartilage from OA patients (n =7) were compared on a 30,000 cDNA-fragment array and differentially expressed genes were extracted by subtraction. Expression of selected genes was assessed during in vitro chondrogenic differentiation of MSCs and during dedifferentiation of expanded chondrocytes using quantitative and semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Protein secretion was measured by enzyme-linked immunosorbent assay. Results: Eighty-seven genes were differentially expressed between MSCs and cartilage with a more than three-fold difference. Sixty-seven of them were higher expressed in cartilage and among them 15 genes were previously not detected in cartilage. Differential expression was confirmed for 69% of 26 reanalysed genes by RT-PCR. The profiles of three unknown transcripts and six protease-related molecules were characterised during differentiation. SERPINA1 and SERPINA3 mRNA expression correlated with chondrogenic differentiation of MSCs and dedifferentiation of chondrocytes, and SERPINA1 protein levels in culture supernatants could be correlated alike. Conclusions: cDNA-array analysis identified SERPINA1 and A3 as new differentiation-relevant genes for cartilage. Since SERPINA1 secretion correlated with both chondrogenesis of MSCs and dedifferentiation during chondrocyte expansion, it represents an attractive marker for refinement of chondrocyte differentiation. [Copyright &y& Elsevier]

OBJECTIVE: Renal involvement in systemic lupus erythematosus (SLE) is associated with poor prognosis. Currently available renal biomarkers are relatively insensitive and nonspecific for diagnosing SLE nephritis. Previous research suggests that neutrophil gelatinase-associated lipocalin (NGAL) is a high-quality renal biomarker of acute kidney injury, while its usefulness in SLE is unclear. We undertook this study to determine the relationship between urinary NGAL excretion and SLE disease activity or damage, with a focus on nephritis. METHODS: A cohort of 35 patients diagnosed as having SLE prior to age 16 years (childhood-onset SLE) was assessed for disease activity (using the Systemic Lupus Erythematosus Disease Activity Index 2000 update) and damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLE Damage Index) in a double-blind, cross-sectional study. Information on current markers of renal function and disease was obtained and compared with NGAL levels (ng/mg of urinary creatinine) measured by enzyme-linked immunosorbent assay. Eight children with juvenile idiopathic arthritis (JIA) served as controls. RESULTS: NGAL levels did not differ with the age, weight, height, sex, or race of the patients. Patients with childhood-onset SLE had significantly higher NGAL levels than did those with JIA (P < 0.0001). NGAL levels were strongly to moderately correlated with renal disease activity and renal damage (Spearman's r >/= 0.47, P < 0.0001 for both comparisons), but not with extrarenal disease activity or extrarenal damage. NGAL levels of >0.6 ng/mg urinary creatinine were 90% sensitive and 100% specific for identifying childhood-onset SLE patients with biopsy-proven nephritis. CONCLUSION: Urinary NGAL is a promising potential biomarker of childhood-onset SLE nephritis. The results of the current study require validation in a larger cohort to more accurately delineate urinary NGAL excretion in relation to the diverse SLE phenotypes. [ABSTRACT FROM AUTHOR]

Objectives: To develop scales assessing acceptability of human papillomavirus (HPV) testing in adolescents, to compare acceptability of self to clinician testing, and to identify adolescent characteristics associated with acceptability.Methods: Female adolescents 14-21 years of age attending a hospital based teen health centre self collected vaginal samples and a clinician, using a speculum, collected cervicovaginal samples for HPV DNA. Acceptability of and preferences for self and clinician testing were assessed at baseline and 2 week visits.Results: The mean age of the 121 participants was 17.8 years and 82% were black. The acceptability scales demonstrated good internal consistency, reliability, test-retest reliability, and factorial validity. Scores were significantly lower for self testing than clinician testing on the acceptability scale and three subscales measuring trust of the test result, confidence in one's ability to collect a specimen, and perceived effects of testing (p < 0.01). Of those who reported a preference, 73% preferred clinician to self testing. Acceptability scores for both self and clinician testing increased significantly pre-examination to post-examination (p < 0.01). Multivariable analyses demonstrated that race was independently associated with pre-examination and post-examination acceptability of self testing, and that sexual behaviours and gynaecological experiences were associated with specific acceptability subscales.Conclusions: This sample of adolescents found clinician testing for HPV to be more acceptable than self testing and preferred clinician to self testing. If self testing for HPV is offered in the future, clinicians should not assume that adolescent patients will prefer self testing. Instead, they should educate adolescents about available testing options and discuss any concerns regarding self collection technique or accuracy of test results. [ABSTRACT FROM AUTHOR]

Objective: To analyze the MR imaging features of fibrolipomatous hamartoma (FLH) of nerves.Design and Patients: MR imaging studies from six patients (three men and three women) were retrospectively reviewed by three musculoskeletal radiologists. In four patients, a biopsy of the nerve lesion was performed. In two patients, biopsy data were unavailable and the diagnosis was based on the clinical history combined with the MR imaging findings.Results and Conclusion: MR imaging demonstrated fusiform nerve enlargement that was caused by fatty proliferation and thickening of nerve bundles. Nerve bundles appeared as serpentine tubular structures, hypointense on both T1- and T2-weighted images. The degree of fatty proliferation varied among patients. In addition, significant variation in the distribution of fat along the course of the nerves was noted. In three patients, FLH followed the branching pattern of the nerves, a characteristic pathologic finding. In two patients, intramuscular fat deposition (biceps and tibialis posterior muscles) was present. MR imaging findings of FLH are typical, allowing a confident diagnosis. The variation of fatty proliferation among patients and involved nerves as well as the tendency of the abnormalities to follow the branching pattern of the nerves is well demonstrated with MR imaging. FLH may present as an isolated nerve lesion, may be associated with intramuscular fat deposition, or may occur as a feature of macrodystrophia lipomatosa (MDL). [ABSTRACT FROM AUTHOR]

To analyze the MR imaging features of fibrolipomatous hamartoma (FLH) of nerves. MR imaging studies from six patients (three men and three women) were retrospectively reviewed by three musculo-skeletal radiologists. In four patients, a biopsy of the nerve lesion was performed. In two patients, biopsy data were unavailable and the diagnosis was based on the clinical history combined with the MR imaging findings. MR imaging demonstrated fusiform nerve enlargement that was caused by fatty proliferation and thickening of nerve bundles. Nerve bundles appeared as serpentine tubular structures, hypoin-tense on both T1- and T2-weighted images. The degree of fatty proliferation varied among patients. In addition, significant variation in the distribution of fat along the course of the nerves was noted. In three patients, FLH followed the branching pattern of the nerves, a characteristic pathologic finding. In two patients, intramuscular fat deposition (biceps and tibialis posterior muscles) was present. MR imaging findings of FLH are typical, allowing a confident diagnosis. The variation of fatty proliferation among patients and involved nerves as well as the tendency of the abnormalities to follow the branching pattern of the nerves is well demonstrated with MR imaging. FLH may present as an isolated nerve lesion, may be associated with intramuscular fat deposition, or may occur as a feature of macrodystrophia lipomatosa (MDL). [ABSTRACT FROM AUTHOR]

Ossification of the Achilles tendon is a rare clinical entity that is characterized by the presence of an ossific mass contained within the fibrocartilaginous substance of the tendon. Because the radiographic features of this condition have not been documented entirely and the magnetic resonance (MR) imaging findings have not been determined, a review of 16 affected tendons in 12 patients was performed in an attempt to characterize the imaging abnormalities associated with this process. MR imaging was performed in three Achilles tendons which demonstrated thickening of the tendons at the level of the ossifications and a lack of intratendinous signal abnormalities compatible with acute tendinitis. Signal intensity similar to that of bone marrow was present in the ossifications. [ABSTRACT FROM AUTHOR]

As part of the Iron Overload, Public Health and Genetics conference, sponsored by the Centers for Disease Control and Prevention in March 1997, a working group was convened to consider strategies to increase early case detection of hemochromatosis. This group emphasized that the primary public health goal should be to diagnose hemochromatosis before symptoms appear. To reach this goal, education and action need to be targeted to physicians and other health care workers, laboratorians, administrators, payers, and the public. Strategies to disseminate updated information and increase early case detection were prioritized according to expected effectiveness. Strategies targeting physicians are 1) to identify national and local physician-leaders and 2) to educate physicians about hemochromatosis in basic, graduate specialty, and continuing medical education. Strategies aimed at the health system are 1) to encourage laboratories to provide the transferrin saturation test as part of routine laboratory panels and 2) to work with policymakers and payers to allow reimbursement for case detection. Finally, public education is recommended to increase lay support for the early diagnosis of hemochromatosis. Attempts to educate the public should be aimed first at persons who receive diagnoses of hemochromatosis in order to ensure that they are properly treated and then at asymptomatic persons who could be screened as part of health appraisals. Although identifying physician-leaders and educating physicians are the highest priorities, physicians should not be targeted at the exclusion of payers and the public. Simultaneous efforts to reach all groups in appropriate ways should be initiated to provide the interest and infrastructure necessary to decrease morbidity and mortality from hemochromatosis. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. Methods: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 \(kg/m^2\) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case–control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Results: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, \(p = 8.5 × 10^{−14})\), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, \(p = 1.2 × 10^{−11})\) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, \(p = 8.2 × 10^{−10})\). Conclusions/interpretation We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.