Hypergonadotropic hypogonadism and chromosomal aberrations: clinical heterogeneity and implications on the health of elderly men, case series.

BACKGROUND: Hypogonadism in older men is often considered as late onset hypogonadism. However, this clinical condition results from primary testicular failure which could be of genetic origin with Klinefelter syndrome being the most common chromosomal abnormality associated with it. CASE PRESENTATION: We report a heterogeneous group of cases who were diagnosed with hypergonadotropic hypogonadism in their adulthood and were found to have rare chromosomal aberrations. All were elderly men (in their 70 s and 80 s) for whom the diagnosis was made during the evaluation of incidental symptoms suggestive of endocrinopathy. The first had hyponatremia; the other two had gynaecomastia and features of hypogonadism noted during admission for various acute medical problems. With respect to their genetic results; the first had a male karyotype with balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 7. The second case had a male karotype with one normal X chromosome and an isochrome for the short arm of the Y chromosome. The third case was an XX male with unbalanced translocation between the X & Y chromosomes with retention of the SRY locus. CONCLUSION: Hypergonadotrophic hypogonadism in the elderly, may be due to chromosomal aberrations, resulting in heterogeneous and diverse clinical phenotypes. Vigilance must be exercised when seeing cases with subtle clinical findings. This report suggests that in selected cases of adult hypergonadotropic hypogonadism, chromosomal analysis may be indicated.

A tale of many tumors and one endocrine site: A case series of pituitary metastases.

BACKGROUND: Metastases to the pituitary gland are extremely rare with an incidence rate reported from an autopsy series of 1.8%-12%, and only 20% was diagnosed clinically. Tumors that commonly metastasize are breast and lung tumors. CASE SERIES: We present a series of five cases, including four female patients and one male patient with metastatic cancer. Two women had metastatic small lung cancer and presented with diabetes insipidus (DI). Two women had metastatic breast cancer, of which one presented with DI and the other with panhypopituitarism. The male patient had bronchogenic adenocarcinoma and presented with DI. CONCLUSION: Our case series confirmed earlier reports that DI is the most common presentation of metastases to the pituitary gland.

Comparison of serum and urinary biomarker panels with albumin/creatinine ratio in the prediction of renal function decline in type 1 diabetes.

AIMS/HYPOTHESIS: We examined whether candidate biomarkers in serum or urine can improve the prediction of renal disease progression in type 1 diabetes beyond prior eGFR, comparing their performance with urinary albumin/creatinine ratio (ACR). METHODS: From the population-representative Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) we sampled 50% and 25% of those with starting eGFR below and above 75 ml min-1 [1.73 m]-2, respectively (N = 1629), and with median 5.1 years of follow-up. Multiplexed ELISAs and single molecule array technology were used to measure nine serum biomarkers and 13 urine biomarkers based on our and others' prior work using large discovery and candidate studies. Associations with final eGFR and with progression to <30 ml min-1 [1.73] m-2, both adjusted for baseline eGFR, were tested using linear and logistic regression models. Parsimonious biomarker panels were identified using a penalised Bayesian approach, and their performance was evaluated through tenfold cross-validation and compared with using urinary ACR and other clinical record data. RESULTS: Seven serum and seven urine biomarkers were strongly associated with either final eGFR or progression to <30 ml min-1 [1.73 m]-2, adjusting for baseline eGFR and other covariates (all at p<2.3 × 10-3). Of these, associations of four serum biomarkers were independent of ACR for both outcomes. The strongest associations with both final eGFR and progression to <30 ml min-1 [1.73 m]-2 were for serum TNF receptor 1, kidney injury molecule 1, CD27 antigen, α-1-microglobulin and syndecan-1. These serum associations were also significant in normoalbuminuric participants for both outcomes. On top of baseline covariates, the r2 for prediction of final eGFR increased from 0.702 to 0.743 for serum biomarkers, and from 0.702 to 0.721 for ACR alone. The area under the receiver operating characteristic curve for progression to <30 ml min-1 [1.73 m]-2 increased from 0.876 to 0.953 for serum biomarkers, and to 0.911 for ACR alone. Other urinary biomarkers did not outperform ACR. CONCLUSIONS/INTERPRETATION: A parsimonious panel of serum biomarkers easily measurable along with serum creatinine may outperform ACR for predicting renal disease progression in type 1 diabetes, potentially obviating the need for urine testing.

Small changes in calcium replacement therapy triggering hypercalcaemia and rising creatinine - a case series.

In this article, we present four cases of renal failure secondary to hypercalcaemia which were brought to the attention of our hospital's nephrology team. These happened in the setting of simple medication changes for hypoparathyroidism post-thyroid surgery. These cases have in common minor changes in preparations leading to significant adverse events. In two cases, excipient changes were the only changes identified in the patients' regimen. In all cases, cessation of the offending calcium preparation and treatment with IV rehydration led to a return to baseline creatinine levels. Communicating to patients the importance of consistency in how calcium and vitamin D supplements are taken is crucial in preventing adverse effects. Prescribers should be aware of excipient changes and that these are not always clinically insignificant.

Selenoprotein Gene Nomenclature.

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.

Chiral Brønsted Acid Catalyzed Cascade Alcohol Deprotection and Enantioselective Cyclization.

The protection-deprotection sequence is vital to organic synthesis. Here, we describe a novel catalytic cascade where a chiral Brønsted acid selectively removes ether protecting groups and catalyzes intramolecular cyclization in one pot. We tested three model substrates from our previous work and investigated the rate of deprotection through gas chromatography (GC) studies. This work builds on our stereoselective synthesis of lactones by streamlining our synthesis. It also opens the door for additional investigations into other catalytic cascade reactions using chiral Brønsted acid catalysts.

Genetic variants associated with Lp(a) lipoprotein level and coronary disease.

BACKGROUND: An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.

Boosting and lassoing new prostate cancer SNP risk factors and their connection to selenium.

We begin by arguing that the often used algorithm for the discovery and use of disease risk factors, stepwise logistic regression, is unstable. We then argue that there are other algorithms available that are much more stable and reliable (e.g. the lasso and gradient boosting). We then propose a protocol for the discovery and use of risk factors using lasso or boosting variable selection. We then illustrate the use of the protocol with a set of prostate cancer data and show that it recovers known risk factors. Finally, we use the protocol to identify new and important SNP based risk factors for prostate cancer and further seek evidence for or against the hypothesis of an anticancer function for Selenium in prostate cancer. We find that the anticancer effect may depend on the SNP-SNP interaction and, in particular, which alleles are present.

Comparison of DNA methylation clocks in Black South African men.

Aims: DNA methylation clocks are widely used to estimate biological age, although limited data are available on non-European ethnicities. This manuscript characterizes the behavior of five DNA methylation clocks in 120 older Black South African men. Methods: The age estimation accuracy of the Horvath, Hannum and skin and blood clocks and the relative age-related mortality risk and predicted time to death portrayed by the PhenoAge and GrimAge biomarkers are investigated, respectively. Results: The results confirm the tendency of DNA methylation clocks to underestimate the biological age of older individuals. GrimAge more accurately characterizes biological decline in this African cohort compared with PhenoAge owing to the unique inclusion of smoking-related damage in the GrimAge estimate. Conclusions: Each clock provides a different fraction of information regarding the aging body. It is essential to continue studying under-represented population groups to ensure methylation-derived indicators are robust and useful in all populations.

Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p.

Genome-wide association studies have identified a region on chromosome 9p that is associated with coronary artery disease (CAD). The region is also associated with type 2 diabetes (T2D), a risk factor for CAD, although different SNPs were reported to be associated to each disease in separate studies. We have undertaken a case-control study in 4251 CAD cases and 4443 controls in four European populations using previously reported ('literature') and tagging SNPs. We replicated the literature SNPs (P = 8x10(-13); OR = 1.29; 95% CI: 1.20-1.38) and showed that the strong consistent association detected by these SNPs is a consequence of a 'yin-yang' haplotype pattern spanning 53 kb. There was no evidence of additional CAD susceptibility alleles over the major risk haplotype. CAD patients without myocardial infarction (MI) showed a trend towards stronger association than MI patients. The CAD susceptibility conferred by this locus did not differ by sex, age, smoking, obesity, hypertension or diabetes. A simultaneous test of CAD and diabetes susceptibility with CAD and T2D-associated SNPs indicated that these associations were independent of each other. Moreover, this region was not associated with differences in plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fibrinogen, albumin, uric acid, bilirubin or homocysteine, although the CAD-high-risk allele was paradoxically associated with lower triglyceride levels. A large antisense non-coding RNA gene (ANRIL) collocates with the high-risk haplotype, is expressed in tissues and cell types that are affected by atherosclerosis and is a prime candidate gene for the chromosome 9p CAD locus.

Methylation vs. Protein Inflammatory Biomarkers and Their Associations With Cardiovascular Function.

DNA methylation data can be used to estimate proportions of leukocyte subsets retrospectively, when directly measured cell counts are unavailable. The methylation-derived neutrophil-to-lymphocyte and lymphocyte-to-monocyte ratios (mdNLRs and mdLMRs) have proven to be particularly useful as indicators of systemic inflammation. As with directly measured NLRs and LMRs, these methylation-derived ratios have been used as prognostic markers for cancer, although little is known about them in relation to other disorders with inflammatory components, such as cardiovascular disease (CVD). Recently, methylation of five genomic cytosine-phosphate-guanine sites (CpGs) was suggested as proxies for mdNLRs, potentially providing a cost-effective alternative when whole-genome methylation data are not available. This study compares seven methylation-derived inflammatory markers (mdNLR, mdLMR, and individual CpG sites) with five conventionally used protein-based inflammatory markers (C-reactive protein, interleukins 6 and 10, tumor-necrosis factor alpha, and interferon-gamma) and a protein-based inflammation score, in their associations with cardiovascular function (CVF) and risk. We found that markers of CVF were more strongly associated with methylation-derived than protein-based markers. In addition, the protein-based and methylation-derived inflammatory markers complemented rather than proxied one another in their contribution to the variance in CVF. There were no strong correlations between the methylation and protein markers either. Therefore, the methylation markers could offer unique information on the inflammatory process and are not just surrogate markers for inflammatory proteins. Although the five CpGs mirrored the mdNLR well in their capacity as proxies, they contributed to CVF above and beyond the mdNLR, suggesting possible added functional relevance. We conclude that methylation-derived indicators of inflammation enable individuals with increased CVD risk to be identified without measurement of protein-based inflammatory markers. In addition, the five CpGs investigated here could be useful surrogates for the NLR when the cost of array data cannot be met. Used in tandem, methylation-derived and protein-based inflammatory markers explain more variance than protein-based inflammatory markers alone.

Diabetic Neuropathy Is a Substantial Burden in People With Type 1 Diabetes and Is Strongly Associated With Socioeconomic Disadvantage: A Population-Representative Study From Scotland.

OBJECTIVE: To assess the contemporaneous prevalence of diabetic peripheral neuropathy (DPN) in people with type 1 diabetes (T1D) in Scotland and study its cross-sectional association with risk factors and other diabetic complications. RESEARCH DESIGN AND METHODS: We analyzed data from a large representative sample of adults with T1D (N = 5,558). We assessed the presence of symptomatic neuropathy using the dichotomized (≥4) Michigan Neuropathy Screening Instrument Patient Questionnaire score. Logistic regression models were used to investigate associations between DPN and risk factors, as well as with other complications. RESULTS: The burden of DPN is substantial with 13% prevalence overall. Adjusting for attained age, diabetes duration, and sex, the odds of DPN increased mainly with waist-to-hip ratio, lipids, poor glycemic control (odds ratio 1.51 [95% CI 1.21-1.89] for levels of 75 vs. 53 mmol/mol), ever versus never smoking (1.67 [1.37-2.03]), and worse renal function (1.96 [1.03-3.74] for estimated glomerular filtration rate levels <30 vs. ≥90 mL/min/1.73 m2). The odds significantly decreased with higher HDL cholesterol (0.77 [0.66-0.89] per mmol/L). Living in more deprived areas was associated with DPN (2.17 [1.78-2.65]) for more versus less deprived areas adjusted for other risk factors. Finally, individuals with prevalent DPN were much more likely than others to have other diabetes complications. CONCLUSIONS: Diabetic neuropathy remains substantial, particularly affecting those in the most socioeconomically deprived groups. Those with clinically manifest neuropathy also have a higher burden of other complications and elevated levels of modifiable risk factors. These data suggest that there is considerable scope to reduce neuropathy rates and narrow the socioeconomic differential by better risk factor control.

Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17.

Coronary artery disease (CAD) is a leading cause of death world-wide, and most cases have a complex, multifactorial aetiology that includes a substantial heritable component. Identification of new genes involved in CAD may inform pathogenesis and provide new therapeutic targets. The PROCARDIS study recruited 2,658 affected sibling pairs (ASPs) with onset of CAD before age 66 y from four European countries to map susceptibility loci for CAD. ASPs were defined as having CAD phenotype if both had CAD, or myocardial infarction (MI) phenotype if both had a MI. In a first study, involving a genome-wide linkage screen, tentative loci were mapped to Chromosomes 3 and 11 with the CAD phenotype (1,464 ASPs), and to Chromosome 17 with the MI phenotype (739 ASPs). In a second study, these loci were examined with a dense panel of grid-tightening markers in an independent set of families (1,194 CAD and 344 MI ASPs). This replication study showed a significant result on Chromosome 17 (MI phenotype; p = 0.009 after adjustment for three independent replication tests). An exclusion analysis suggests that further genes of effect size lambda(sib) > 1.24 are unlikely to exist in these populations of European ancestry. To our knowledge, this is the first genome-wide linkage analysis to map, and replicate, a CAD locus. The region on Chromosome 17 provides a compelling target within which to identify novel genes underlying CAD. Understanding the genetic aetiology of CAD may lead to novel preventative and/or therapeutic strategies.

N-Glycan Profile and Kidney Disease in Type 1 Diabetes.

OBJECTIVE: Poorer glycemic control in type 1 diabetes may alter N-glycosylation patterns on circulating glycoproteins, and these alterations may be linked with diabetic kidney disease (DKD). We investigated associations between N-glycans and glycemic control and renal function in type 1 diabetes. RESEARCH DESIGN AND METHODS: Using serum samples from 818 adults who were considered to have extreme annual loss in estimated glomerular filtration rate (eGFR; i.e., slope) based on retrospective clinical records, from among 6,127 adults in the Scottish Diabetes Research Network Type 1 Bioresource Study, we measured total and IgG-specific N-glycan profiles. This yielded a relative abundance of 39 total (GP) and 24 IgG (IGP) N-glycans. Linear regression models were used to investigate associations between N-glycan structures and HbA1c, albumin-to-creatinine ratio (ACR), and eGFR slope. Models were adjusted for age, sex, duration of type 1 diabetes, and total serum IgG. RESULTS: Higher HbA1c was associated with a lower relative abundance of simple biantennary N-glycans and a higher relative abundance of more complex structures with more branching, galactosylation, and sialylation (GP12, 26, 31, 32, and 34, and IGP19 and 23; all P < 3.79 × 10-4). Similar patterns were seen for ACR and greater mean annual loss of eGFR, which were also associated with fewer of the simpler N-glycans (all P < 3.79 × 10-4). CONCLUSIONS: Higher HbA1c in type 1 diabetes is associated with changes in the serum N-glycome that have elsewhere been shown to regulate the epidermal growth factor receptor and transforming growth factor-ß pathways that are implicated in DKD. Furthermore, N-glycans are associated with ACR and eGFR slope. These data suggest that the role of altered N-glycans in DKD warrants further investigation.

Multiple QTL influence the serum Lp(a) concentration: a genome-wide linkage screen in the PROCARDIS study.

The serum concentration of lipoprotein Lp (a) is known to be highly heritable and associated with cardiovascular risk. A genome-wide variance component linkage analysis was performed to localise quantitative trait loci (QTLs) influencing Lp(a) levels in a large cohort collected in the PROCARDIS coronary heart disease study. Highly significant linkage was detected at the previously described LP(a) locus on chromosome 6q27 (LOD 108). Taking into account the effect of the locus detected on chromosome 6, a highly significant LOD score was detected on chromosome 13q22-31 (LOD 7.0). Another significant region of linkage was observed on chromosomes 11p14-15 (LOD 3.5). The significant peak at 13q22-31 shows an essential overlap with a locus modulating cholesterol in familial hypercholesterolemia. If the gene underlying these loci is the same, it will be a promising candidate target for manipulating LDL-cholesterol and Lp(a). We also detected linkage at a previously identified locus influencing Lp(a) on chromosome 1q23 (LOD 1.5). Our findings provide new and confirmatory information about genomic regions involved in the quantitative variation of Lp(a) and serve as a basis for further studies of candidate genes in these regions.

Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity.

Most of diabetic cardiovascular complications are attributed to endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum (ER) and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes. Hemeoxygenase-1 (HO-1) was shown to protect against oxidative stress in diabetes; however, its role in alleviating ER stress-induced endothelial dysfunction remains not fully elucidated. We aim here to test the protective role of HO-1 against high glucose-mediated ER stress and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death. Human Umbilical Vein Endothelial Cells (HUVECs) were grown in either physiological or intermittent high concentrations of glucose for 5days in the presence or absence of Cobalt (III) Protoporphyrin IX chloride (CoPP, HO-1 inducer) or 4-Phenyl Butyric Acid (PBA, ER stress inhibitor). Using an integrated cellular and molecular approach, we then assessed ER stress and inflammatory responses, in addition to apoptosis and angiogenic capacity in these cells. Our results show that HO-1 induction prevented high glucose-mediated increase of mRNA and protein expression of key ER stress markers. Cells incubated with high glucose exhibited high levels of oxidative stress, activation of major inflammatory and apoptotic responses [nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK)] and increased rate of apoptosis; however, cells pre-treated with CoPP or PBA were fully protected. In addition, high glucose enhanced caspases 3 and 7 cleavage and activity and augmented cleaved poly ADP ribose polymerase (PARP) expression whereas HO-1 induction prevented these effects. Finally, HO-1 induction and ER stress inhibition prevented high glucose-induced reduction in NO release and impaired the angiogenic capacity of HUVECs, and enhanced vascular endothelial growth factor (VEGF)-A expression. Altogether, we show here the critical role of ER stress-mediated cell death in diabetes-induced endothelial dysfunction and impaired angiogenesis and underscore the role of HO-1 induction as a key therapeutic modulator for ER stress response in ischemic disorders and diabetes. Our results also highlight the complex interplay between ER stress response and oxidative stress.

Fibrinogen and clot-related phenotypes determined by fibrinogen polymorphisms: Independent and IL-6-interactive associations.

Interleukin-6 (IL-6) induces the expression of fibrinogen, and polymorphic variation within the fibrinogen genes is believed to alter the magnitude of this expression. The identification of the functional relevance of individual fibrinogen single nucleotide polymorphisms (SNPs) has been hindered by the high linkage disequilibrium (LD) reported in the European fibrinogen gene locus. This study investigated two novel and 12 known fibrinogen SNPs of potential functional relevance, in 2010 Tswana individuals known to have low LD. We aimed to identify functional polymorphisms that contribute to clot-related phenotypes and total and γ' fibrinogen concentrations independently and through their interaction with IL-6, by taking advantage of the high fibrinogen and IL-6 concentrations and the low LD reported in black South Africans. Fibrinogen was significantly associated with IL-6, thereby mediating associations of IL-6 with clot formation and structure, although attenuating the association of IL-6 with clot lysis time. None of the common European fibrinogen haplotypes was present in this study population. Putative functional fibrinogen SNPs FGB-rs7439150, rs1800789 (-1420G/A) and rs1800787 (-148C/T) were significantly associated with fibrinogen concentration and altered clot properties, with several associations significantly influenced by IL-6 concentrations. The impact of harbouring several minor fibrinogen SNP alleles on the association of IL-6 and fibrinogen concentration was cumulative, with possession of each additional minor allele showing a stronger relationship of IL-6 with fibrinogen. This was also reflected in differences in clot properties, suggesting potential clinical relevance. Therefore, when investigating the effect of fibrinogen genetics on fibrinogen concentrations and CVD outcome, the possible interactions with modulating factors and the fact that SNP effects seem to be additive should be taken into account.

A cluster randomised trial, cost-effectiveness analysis and psychosocial evaluation of insulin pump therapy compared with multiple injections during flexible intensive insulin therapy for type 1 diabetes: the REPOSE Trial.

BACKGROUND: Insulin is generally administered to people with type 1 diabetes mellitus (T1DM) using multiple daily injections (MDIs), but can also be delivered using infusion pumps. In the UK, pumps are recommended for patients with the greatest need and adult use is less than in comparable countries. Previous trials have been small, of short duration and have failed to control for training in insulin adjustment. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of pump therapy compared with MDI for adults with T1DM, with both groups receiving equivalent structured training in flexible insulin therapy. DESIGN: Pragmatic, multicentre, open-label, parallel-group cluster randomised controlled trial, including economic and psychosocial evaluations. After participants were assigned a group training course, courses were randomly allocated in pairs to either pump or MDI. SETTING: Eight secondary care diabetes centres in the UK. PARTICIPANTS: Adults with T1DM for > 12 months, willing to undertake intensive insulin therapy, with no preference for pump or MDI, or a clinical indication for pumps. INTERVENTIONS: Pump or MDI structured training in flexible insulin therapy, followed up for 2 years. MDI participants used insulin analogues. Pump participants used a Medtronic Paradigm® VeoTM (Medtronic, Watford, UK) with insulin aspart (NovoRapid, Novo Nordisk, Gatwick, UK). MAIN OUTCOME MEASURES: Primary outcome - change in glycated haemoglobin (HbA1c) at 2 years in participants whose baseline HbA1c was ≥ 7.5% (58 mmol/mol). Key secondary outcome - proportion of participants with HbA1c ≤ 7.5% at 2 years. Other outcomes at 6, 12 and 24 months - moderate and severe hypoglycaemia; insulin dose; body weight; proteinuria; diabetic ketoacidosis; quality of life (QoL); fear of hypoglycaemia; treatment satisfaction; emotional well-being; qualitative interviews with participants and staff (2 weeks), and participants (6 months); and ICERs in trial and modelled estimates of cost-effectiveness. RESULTS: We randomised 46 courses comprising 317 participants: 267 attended a Dose Adjustment For Normal Eating course (132 pump; 135 MDI); 260 were included in the intention-to-treat analysis, of which 235 (119 pump; 116 MDI) had baseline HbA1c of ≥ 7.5%. HbA1c and severe hypoglycaemia improved in both groups. The drop in HbA1c% at 2 years was 0.85 on pump and 0.42 on MDI. The mean difference (MD) in HbA1c change at 2 years, at which the baseline HbA1c was ≥ 7.5%, was -0.24% [95% confidence interval (CI) -0.53% to 0.05%] in favour of the pump (p = 0.098). The per-protocol analysis showed a MD in change of -0.36% (95% CI -0.64% to -0.07%) favouring pumps (p = 0.015). Pumps were not cost-effective in the base case and all of the sensitivity analyses. The pump group had greater improvement in diabetes-specific QoL diet restrictions, daily hassle plus treatment satisfaction, statistically significant at 12 and 24 months and supported by qualitative interviews. LIMITATION: Blinding of pump therapy was not possible, although an objective primary outcome was used. CONCLUSION: Adding pump therapy to structured training in flexible insulin therapy did not significantly enhance glycaemic control or psychosocial outcomes in adults with T1DM. RESEARCH PRIORITY: To understand why few patients achieve a HbA1c of < 7.5%, particularly as glycaemic control is worse in the UK than in other European countries. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61215213. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 20. See the NIHR Journals Library website for further project information.

Genotype at the -174G/C polymorphism of the interleukin-6 gene is associated with common carotid artery intimal-medial thickness: family study and meta-analysis.

BACKGROUND AND PURPOSE: Studies in unrelated individuals have produced conflicting findings concerning the putative association between the interleukin-6 (IL-6) -174G/C polymorphism and carotid intimal-medial thickness (IMT). We have used a family-based genetic association design to assess the heritability of carotid IMT and to investigate the hypothesized association of carotid IMT with the IL-6 to -174G/C polymorphism. METHODS: We studied 854 members of 224 white British families. The heritability of carotid IMT was determined using Multipoint Engine for Rapid Likelihood Inference. Genetic association analyses were carried out using ANOVA and family-based tests of association implemented in Quantitative Transmission Disequilibrium Test. A meta-analysis of previous studies of the association was conducted to place our result in context. RESULTS: The heritability of carotid IMT was 24%. Under a recessive model (GG+GC versus CC), there was significant evidence of association between IL-6 to the -174G/C genotype and adjusted log(e) maximal carotid IMT (F=5.469; P=0.02). Family-based analyses using Quantitative Transmission Disequilibrium Test showed no evidence of population stratification as a cause of the observed association (chi2(1)=0.469; P=0.4934). The CC genotype was associated with a 4.8% increase in maximal carotid IMT and accounted for 0.6% of the observed variation in the trait, which is equivalent to 2.5% of the heritable component. A meta-analysis of the present and 2 previous large studies, which enrolled a total of 2930 subjects, confirmed the recessive effect of the C allele on carotid IMT (P=0.0014). CONCLUSIONS: The genotype at the IL-6 to -174G/C polymorphism is associated with common carotid artery IMT, although the size of the genetic effect is small.

A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein.

The plasma CRP concentration has consistently been shown to be associated with the risk of future coronary heart disease (CHD) and recent studies have suggested that CRP has a pathogenic role in CHD. Family studies and genotype-phenotype association studies of known polymorphisms in the intron, second exon and 3'-untranslated region (UTR) have suggested that plasma CRP concentrations are under genetic control. However, no functional polymorphisms have so far been reported in the promoter region of the CRP gene. Screening of 1600 base pair (bp) of the promoter region of the CRP gene, using denaturing high performance liquid chromatography, revealed two novel common single nucleotide polymorphisms (SNPs). One of them, a three allelic SNP located at position -286 from the transcription start, was strongly associated with the plasma CRP concentration, predominantly in patients with CHD. No difference in allele frequency was seen between middle-aged post-infarction patients and population-based controls. The prognostic role and therapeutic implications in CHD and the functionality of this polymorphism remain to be determined.