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Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have proven efficacy in improving cardiovascular outcomes. Roles for the PCSK9 molecule in metabolic pathways beyond LDL receptor processing and cholesterol homeostasis are well established. PCSK9 genetic variants associated with lower LDL-C levels correlate with a higher incidence of type 2 diabetes (T2DM), calling into question the appropriateness of these drugs in patients with T2DM and those at high risk of developing diabetes, and whether cardiovascular benefit seen with PCSK9 inhibitors might be offset by resultant dysglycemia. The purpose of this review was to examine the role of PCSK9 protein in glucose homeostasis, the impact of PCSK9 inhibition in relation to glucose homeostasis, and whether some of the cardiovascular benefit seen with PCSK9 inhibitors and statins might be offset by resultant dysglycemia.Comprehensive literature searches of electronic databases of PubMed, EMBASE, and OVID were conducted by using the search terms hyperlipidaemia, PCSK9, diabetes, and glucose as well as other relevant papers of interest collected by the authors. The retrieved papers were reviewed and shortlisted most relevant ones.Genetically determined lower circulating LDL-C and PCSK9 concentrations may have an incremental effect in increasing T2DM incidence, but any perceived harm is outweighed by the reduced risk of atherosclerotic cardiovascular disease achieved through lower lifetime exposure to LDL-C. PCSK9 monoclonal antibodies are effective and safe in patients with T2DM and those at high risk of developing it. The number-needed-to-treat to prevent one atherosclerotic cardiovascular disease event in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study in the subgroup with diabetes is significantly lower than for those without. Therefore, T2DM or being at high risk to develop it should not be a reason to avoid these agents. The safety of PCSK9 inhibition in relation to glucose homeostasis may depend on the method of inhibition and whether it occurs in circulation or the cells. Data from experimental studies and randomized controlled trials suggest no detrimental effect of PCSK9 monoclonal antibodies on glucose homeostasis. More data and large randomized controlled studies are needed to assess the impact of other methods of PCSK9 inhibition on glucose homeostasis.PCSK9monoclonal antibodies markedly reduce LDL-C and consistently reduce cardiovascular mortality in patients with and without diabetes. Current evidence does not suggest an adverse effect of PCSK9 monoclonal antibodies on glycemic parameters.

Flash glucose monitoring (FGM) and real-time continuous glucose monitoring (RT-CGM) are increasingly used in clinical practice, with improvements in HbA1c and time in range (TIR) reported in clinical studies. We aimed to evaluate the impact of FGM and RT-CGM use on glycaemic outcomes in adults with type 1 diabetes (T1DM) under routine clinical care. We performed a retrospective data analysis from electronic outpatient records and proprietary web-based glucose monitoring platforms. We measured HbA1c (pre-sensor vs. on-sensor data) and sensor-based outcomes from the previous three months as per the international consensus on RT-CGM reporting guidelines. Amongst the 789 adults with T1DM, HbA1c level decreased from 61.0 (54.0, 71.0) mmol/mol to 57 (49, 65.8) mmol/mol in 561 people using FGM, and from 60.0 (50.0, 70.0) mmol/mol to 58.8 (50.3, 66.8) mmol/mol in 198 using RT-CGM (p &lt, 0.001 for both). We found that 23% of FGM users and 32% of RT-CGM users achieved a time-in-range (TIR) (3.9 to 10 mmol/L) of &gt, 70%. For time-below-range (TBR) &lt, 4 mmol/L, 70% of RT-CGM users and 58% of FGM users met international recommendations of &lt, 4%. Our data add to the growing body of evidence supporting the use of FGM and RT-CGM in T1DM.

Aims People with type 1 diabetes (T1D) face the daily task of implementing self-management strategies to achieve their glycaemic goals. The UK COVID-19 lockdown has had an impact on day-to-day behaviour, which may affect diabetes self-management and outcomes. We assessed whether sensor-based outcomes pre- and during lockdown periods were different in a cohort of glucose sensor users with T1D. Methods Data were collected from Freestyle Libre (FSL) or Dexcom G6 sensor users who remotely shared their data with the diabetes clinic web platform. Sensor metrics according to international consensus were analysed and compared between pre-lockdown period and 2 and 3 weeks into lockdown (periods 1 and 2). Results Two hundred and sixty-nine T1D patients (baseline HbA1c 57 ± 14 mmol/mol) were identified as FSL (n = 190) or Dexcom G6 (n = 79) users. In patients with sensor use > 70% (N = 223), compared to pre-lockdown period percentage TIR 3.9–10 mM (TIR) significantly increased during period 1 (59.6 ± 18.2 vs. 57.5 ± 17.2%, p = 0.002) and period 2 (59.3 ± 18.3 vs. 57.5 ± 17.2%, p = 0.035). The proportion of patients achieving TIR ≥ 70% increased from 23.3% pre-lockdown to 27.8% in period 1 and 30.5% in period 2. A higher proportion also achieved the recommended time below and above range, and coefficient of variation in periods 1 and 2. Dexcom G6 users had significantly lower % time below range (p Conclusion Sensor-based glycaemic outcomes in people with T1D in the current cohort improved during COVID-19 lockdown, which may be associated with positive changes in self-management strategies. Further work is required to evaluate long-term sustainability and support.

Background & aims The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a worldwide pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients, who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations. Methods Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrate, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen. Results & Conclusions: There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests., Graphical abstract Image 1, Highlights • Patients with known atherosclerotic cardiovascular disease and related comorbidities are at increased risk of severe illness and mortality if infected with COVID-19. • There is no convincing evidence to suggest harm from lipid lowering therapy or on-treatment low LDL cholesterol if patients develop acute illnesses or SARS-CoV-2. In fact, available evidence suggests that statin therapy is associated with benefits. • Patients treated for hyperlipidaemia should not interrupt their treatment because of COVID-19 pandemic. • Continue lipid lowering therapy in patients with confirmed diagnosis of COVID-19 unless possible risks outweigh benefits. • In patient treated for COVID-19 with pharmacologic agents, drug interactions with lipid lowering therapies should be investigated and assessed.

Lipids, along with proteins and carbohydrates, play a major role in metabolism. They are defined as oils, waxes, fatty acids, and cholesterol. Lipids have a particular role in the physiology of energy metabolism and in the formation of steroid hormones. They are also involved in intracellular signaling, in modulating nerve function, and are responsible for the structural integrity of the cell membrane. In addition, they regulate processes such as protein modification and inflammation. To enable such a diverse range of functions, the pathways of lipid metabolism are closely regulated and also integrated with nonlipid pathways. In order to transport lipids through a predominantly aqueous environment in the body, they are complexed with proteins called apolipoproteins to form macromolecular structures called lipoproteins. The apolipoproteins also function as ligands to enable the interaction between lipoproteins and their receptors and play a role as inhibitors or cofactors for enzymes involved in lipid metabolism.

Hypercholesterolaemia is amongst the most common conditions encountered in the medical profession. It remains one of the key modifiable cardiovascular risk factors and there have been recent advances in the risk stratification methods and treatment options available. In this review, we provide a background into hypercholesterolaemia for non-specialists and consider the merits of the different risk assessment tools available. We also provide detailed considerations as to: i) when to start treatment, ii) what targets to aim for and iii) the role of low density lipoprotein cholesterol.

A 21-year-old woman presented to hospital with abdominal pain and nausea. She had a history of Graves’ disease which had been effectively treated with carbimazole for 15 months. Investigations revealed a serum adjusted calcium level of 3.69 mmol/L with a suppressed parathyroid hormone, thyroid stimulating hormone

Background and aims Untreated individuals with familial hypercholesterolaemia (FH) are at increased risk of developing premature cardiovascular disease (CVD). Early diagnosis and treatment can result in a normal life expectancy. A recent survey commissioned by the European Atherosclerosis Society (EAS) reported a lack of awareness of FH in the general population. We conducted a survey to assess knowledge among healthcare professionals involved in the assessment and management of cardiovascular risk and disease in the United Kingdom. Methods A survey designed to assess knowledge of diagnostic criteria, risk assessment, the role of cascade screening, and management options for patients with FH was distributed to 1000 healthcare professionals (response rate 44.3%). The same survey was redistributed following attendance at an educational session on FH. Results 151 respondents (40.5%) reported having patients under their care who would meet the diagnostic criteria for FH, but just 61.4% recognized that cardiovascular risk estimation tools cannot be applied in FH, and only 22.3% understood the relative risk of premature CVD compared to the general population. Similarly, just 65.9% were aware of recommendations regarding cascade screening. Conclusions The prevalence and associated risk of FH continue to be underestimated, and knowledge of diagnostic criteria and treatment options is suboptimal. These results support the recent Consensus Statement of the EAS and production of quality standards by the National Institute for Health and Care Excellence. Further work is required to formulate interventions to improve FH awareness and knowledge, and to determine the effect these interventions have on patient outcomes.

Dyslipidaemia is an important cardiovascular disease risk factor. Many drugs affect lipid profile and lipoprotein metabolism. We reviewed unintended effects of nonlipid modifying, commonly used medications on lipid profile and lipoprotein metabolism.Several detrimental effects of many drug classes such as diuretics, antidepressant, anticonvulsant and antiretroviral drugs have been reported, whereas other drug classes such as antiobesity, alpha 1-blockers, oestrogens and thyroid replacement therapy were associated with positive effects.Dyslipidaemia is a common side-effect of many medications. This should be taken into consideration, especially in patients at high risk of cardiovascular disease. Other drugs demonstrated positive effects on circulating lipids and lipoproteins. The impact of these unintended effects on atherosclerotic disease risk and progression is unclear.

Purpose To assess the effect of applying a protocol for image selection and the number of images required for adequate quantification of corneal nerve pathology using in vivo corneal confocal microscopy (IVCCM). Methods IVCCM was performed in 35 participants by a single examiner. For each participant, 4 observers used a standardized protocol to select 6 central corneal nerve images to assess the inter-observer variability. Furthermore, images were selected by a single observer on two occasions to assess intra-observer variability and the effect of sample size was assessed by comparing 6 with 12 images. Corneal nerve fiber density (CNFD), branch density (CNBD) and length (CNFL) were quantified using fully automated software. The data were compared using the intra class correlation coefficient (ICC) and Bland-Altman agreement plots for all experiments. Results The ICC values for CNFD, CNBD and CNFL were 0.93 (P

Background: Statin therapy is recommended in type 2 diabetes (T2DM) although views on treatment intensity and therapeutic targets remain divided. Objectives: Our objectives were to compare the effects of high-intensity and moderate-intensity atorvastatin treatment on lipoprotein metabolism and inflammatory markers and how frequently treatment goals are met in high-risk T2DM patients. Methods: Patients with T2DM and albuminuria (urinary albumin:creatinine ratio >5 mg/mmol, total cholesterol

We sought to identify circulating microRNAs as biomarkers of prevalent or incident diabetes. In a pilot study of 18 sex- and age-matched patients with metabolic syndrome, nine of whom developed diabetes during 6 years of follow-up, an array of 372 microRNAs discovered significantly elevated serum levels of microRNAs -122, -192, -194, and -215 in patients who developed diabetes mellitus type 2 (T2DM). In two cross-sectional validation studies, one encompassing sex- and age-matched groups of patients with T2DM, impaired fasting glucose (IFG) and euglycemic controls (n = 43 each) and the other 53 patients with type 1 diabetes and 54 age- and BMI-matched euglycemic controls, serum levels of miR-192, miR-194, and mi215 were significantly higher in diabetic subjects than in probands with euglycemia or IFG. In a longitudinal study of 213 initially diabetes-free patients of whom 35 developed diabetes during 6 years of follow-up, elevated serum levels of microRNAs 192 and 194 were associated with incident T2DM, independently of fasting glucose, HbA1c and other risk factors. Serum levels of miR-192 and miR-194 were also elevated in diabetic Akt2 knockout mice compared to wild type mice. In conclusion, circulating microRNAs -192 and -194 are potential biomarkers for risk of diabetes.

Familial hypercholesterolemia results from gene mutations approximately halving the number of functional LDL receptors in heterozygotes and a greater lack in homozygotes. Reduced receptor-mediated catabolism of LDL causes high plasma LDL cholesterol (LDL-C) and premature coronary artery disease. Statins lower plasma cholesterol by upregulating LDL receptor gene expression and are consequently relatively ineffective in homozygous familial hypercholesterolemia (HoFH). The standard treatment for HoFH is LDL apheresis combined with maximum tolerated potent statins, ezetimibe and bile acid sequestrants. In untreated HoFH, coronary heart disease usually develops in the first and second decade of life and often involves the aortic root and aortic valve. Peripheral vascular disease is common. Besides reduced receptor-mediated catabolism, there are other abnormalities in lipid metabolism in HoFH due to lack of LDL receptors. These include increased apoB turnover, raised lipoprotein(a) levels, reduced HDL cholester...

Diabetes mellitus is associated with a considerably increased risk of premature atherosclerotic cardiovascular disease. Intensive glycemic control has essentially failed to significantly improve cardiovascular outcomes in clinical trials. Dyslipidemia is common in diabetes and there is strong evidence that cholesterol lowering improves cardiovascular outcomes, even in patients with apparently unremarkable lipid profiles. Here, the authors review the pathophysiology and implications of the alterations in lipoproteins observed in both type 1 and type 2 diabetes, the effect of medications commonly used in the management of diabetes on the lipid profile, the evidence for lifestyle and pharmaceutical interventions, and national and international recommendations for the management of dyslipidemia in patients with diabetes.

Although the vast majority of thyroid nodules are benign, evaluation by ultrasound-guided fine needle aspiration (FNA) biopsy is usually necessary to exclude underlying malignancy. Partially in recognition of reported variability in FNA sensitivity and specificity, the 2007 British Thyroid Association (BTA) guidelines recommended two benign results 3?6 months apart to exclude neoplasia. The 2014 BTA guidance states that a second FNA is not required for nodules with benign Thy2 cytology and ultrasound characteristics unless there is strong clinical evidence to suggest malignancy. We report a retrospective analysis of patients from two large teaching hospitals who had repeat ultrasound-guided FNA biopsy between 2009 and 2014 following an initial report of Thy2/Thy2c. Radiology and cytology findings for first, second and any subsequent investigations were reviewed. Of the 162 patients with a first FNA of Thy2/2c, 25 repeat biopsies were non-diagnostic (Thy1/1c), and 130 patients again had benign Thy2/2c cytology, although 14 of these repeat biopsies were taken from the opposite side; one of these patients was later diagnosed with an incidental follicular variant of papillary thyroid cancer, another with Hurthle cell adenoma. Seven of the 162 patients with a first FNA of Thy2/2c were found to have Thy3 cytology or higher (3 Thy3a, 2 Thy3, 1 Thy4 and 1 Thy5) on repeat biopsy and progressed to thyroid surgery, where four were diagnosed with thyroid carcinoma. There was no strong clinical evidence to suggest malignancy in any of these patients, and initial ultrasound characteristics were also unremarkable. These results suggest that a second ultrasound-guided FNA biopsy may be necessary to avoid incorrect exclusion of neoplasia in patients initially found to have benign cytology, unless it is proven beyond doubt that by doing so we do not alter clinical outcomes in these generally indolent tumours.

Background The aim of this study was to explore the influence of extended‐release niacin/laropiprant ( ERN / LRP ) versus placebo on high‐density lipoprotein ( HDL ) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)‐containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high‐density lipoprotein cholesterol ( HDL ‐C). Study patients had persistent dyslipidemia despite receiving high‐dose statin treatment. Methods and Results In a randomized double‐blind, placebo‐controlled, crossover trial, we compared the effect of ERN / LRP with placebo in 27 statin‐treated dyslipidemic patients who had not achieved National Cholesterol Education Program‐ ATP III targets for low‐density lipoprotein cholesterol ( LDL ‐C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein ( CETP ) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sd LDL ‐apoB), oxidized LDL (ox LDL ), glycated apoB (glyc‐apoB), lipoprotein phospholipase A2 (Lp‐ PLA 2), lysophosphatidyl choline (lyso‐ PC ), macrophage chemoattractant protein ( MCP 1), serum amyloid A ( SAA ) and myeloperoxidase ( MPO ). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN / LRP was associated with an 18% increase in HDL ‐C levels compared to placebo (1.55 versus 1.31 mmol/L, P LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, ox LDL , Lp‐ PLA 2, lyso‐ PC , MCP 1, and SAA , but no significant changes in glyc‐apoB or sd LDL ‐apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P =0.045), but no change in the antioxidant capacity of HDL in vitro or PON 1 activity. Conclusions ERN / LRP reduces LDL ‐associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL ‐C‐raising effect. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01054508.

Purpose of review To summarize the current evidence about how HDL impedes the oxidative and glycative atherogenic modification of LDL. Recent findings Paraoxonase 1 (PON1) is located on HDL. Meta-analysis of clinical epidemiological investigations reveals a substantial association of low serum PON1 activity with coronary heart disease incidence independent of other risk factors including HDL cholesterol and apolipoprotein AI (apoAI). Transgenic animal models also indicate an antiatherosclerotic role for PON1. However, highly purified and recombinant PON1 do not retain their antioxidant properties. Summary The therapeutic potential of PON1 should be recognized in preventing atherosclerosis and combating infection and organophosphate toxicity. In unleashing this potential, it is important to consider that both highly purified and recombinant PON1 are dissociated from the lipid phase and other components of HDL, such as apoAI and apoM, all of which may be required for HDL (through its PON1 component) to hydrolyze more lipophilic substrates.

Aims Guidelines for primary prevention of cardiovascular disease (CVD) with statins, including the most recent, fail to make the best use of the evidence from clinical trials by concentrating on absolute CVD risk as a statin indication and not also considering that a major determinant of therapeutic benefit is the magnitude of the low-density lipoprotein (LDL) (or non-HDL) cholesterol reduction achieved. This decrease is proportional to the pretreatment concentration. We set out to apply this knowledge to the calculation of the number needed to treat to prevent one event (NNT) and to assess critically how current guidelines performed at different degrees of CVD risk across a range of LDL (or non-HDL) cholesterol concentrations. Methods and results Number needed to treat to prevent one event revealed exclusion from the treatment of some people with higher cholesterol levels, who may benefit more than others needlessly exposed to statins with no realistic prospect of benefit. Furthermore, abandonment of cholesterol therapeutic goals disadvantaged people with higher levels. Conclusion These problems can be overcome by basing the decision to treat on the NNT calculated both from absolute CVD risk and also on the LDL (or non-HDL) cholesterol reduction achievable with statin treatment. This need not adds an additional layer of complexity for the clinician, because computer programmes already used to estimate CVD risk could be easily amended, thus permitting more effective deployment of statins in the population.

Background and aims: We have recently demonstrated that high-density lipoproteins (HDL) transport microRNAs (miRNAs) in the plasma. Here we aim to investigate how HDL-associated miRNAs are regulated in morbidly obese subjects and more importantly, how weight loss after bariatric surgery affected HDL-miRNAs in these subjects. Methods: Plasma HDL were isolated from morbidly obese subjects (n=23) before, 6 months and 12 months after bariatric surgery by immunoprecipitation using goat anti-human apoA-I microbeads. We also isolated HDL from 12 normal subjects using the same methods. miRNAs were extracted from the isolated HDL and miR-223, miR-24 and miR-126 levels were determined by TaqMan miRNA assays. Results: miR-223, miR-24 and miR-126 were present on HDL from obese subjects before and after bariatric surgery. Before surgery, levels of miR-223, miR-24 and miR-126 on HDL from morbidly obese subjects were significantly higher than the levels on HDL from normal subjects. At 12 months after bariatric surgery, miR-223, miR-24 and miR-126 levels on HDL from obese subjects were increased by 2.9-fold, 2.3-fold and 2.7-fold (p Conclusion: HDL-associated miRNAs are differentially regulated in healthy versus morbidly obese subjects. miR-223, miR-24 and miR-126 are sensitive to weight loss induced by bariatric surgery.

High-density lipoprotein cholesterol (HDL-C) concentration is an independent risk factor for cardiovascular disease. Fibrates are widely used in the management of atherogenic dyslipidemia, principally for their triglyceride-lowering and HDL-C–raising effects. Fibrates may cause paradoxical reductions in HDL-C. These reductions are usually modest, but significant reductions have been observed. The molecular mechanism for these paradoxical reductions remains unexplained despite advances in our understanding of lipid metabolism. This review considers possible mechanisms for this effect, illustrated by a patient with an observed reduction in HDL-C of 88% after introduction of fenofibrate.

Aim: The aim of this retrospective analysis was to assess the clinical effectiveness of exenatide in patients with type 2 diabetes in routine clinical practice. Methods: Patients with type 2 diabetes mellitus and inadequate glycemic control were commenced on exenatide in an out-patient setting. Effects on Hba1c, weight and BMI at 3- and 6-month intervals were recorded by a retrospective review of medical records. Results: We examined a cross-section of 61 patients. The mean weight at treatment initiation was 114 kg and baseline Hba1c was 9.8% (84 mmol/mol). Mean reduction in Hba1c at 3 months was 0.8% (10 mmol/mol, P

s / Atherosclerosis 241 (2015) e32ee71 e66 EAS-0517. MODIFICATION OF LIPOPROTEIN AND GLUCOSE METABOLISM, VASCULAR INFLAMMATORY BIOMARKERS AND NEUROPATHY AFTER WEIGHT LOSS FOLLOWING BARIATRIC SURGERY S. Hama , Y. Liu , T. Siahmansur , J. Schofield , S. Azmi , R. Yadav , B. Ammori , R. Malik , H. Soran . 1 Lipoprotein Research Group, University of Manchester, Manchester, United Kingdom; Centre for Endocrinology & Diabetes, University of Manchester, Manchester, United Kingdom; Department of Surgery, Salford Royal Hospital NHS Foundation Trust, Manchester, United Kingdom Aim: To investigate the impact of weight loss following bariatric surgery on lipoproteins, glucose metabolism, vascular inflammatory markers and neuropathy. Methods: 27 obese patients (11 with type 2 diabetes) and 28 healthy controls were recruited. Lipid, glycaemic and vascular biomarkers were measured before, and 6 and 12 months after bariatric surgery. The effect of weight loss on neuropathy was assessed in a subgroup of 10 patients before and 6 months after surgery. Results: After surgery glycated apolipoprotein B (p

Introduction It is well established that glyc-LDL is elevated in the serum of diabetic patients compared to healthy subjects, and that vascular calcification is common in diabetes. Furthermore, recent studies suggest that advanced glycation end products may play a pathogenic role in vascular calcification. We hypothesise that glyc-LDL promotes the osteogenic differentiation of vascular smooth muscle cells in vitro . Methods LDL was isolated from human serum by sequential density gradient ultracentrifugation and incubated at 37°C with a range of glucose concentrations at different time points to determine the optimum glycation conditions. The glyc-LDL was measured using an in-house ELISA method. Bovine Aortic Smooth Muscle Cells (BAoSMCs) were incubated with native or glycated LDL in the presence of osteogenic media and mineral deposition was determined using alizarin red staining and alkaline phosphatase (ALP) activity, which is an early marker of osteogenesis. Results The optimum conditions for LDL glycation was determined as 80mM glucose for 7 days, so these conditions were used for the production of glycated LDL throughout the study. BAoSMCs incubated in osteogenic media exhibited mineralisation after 7 days as determined by alizarin red staining. This calcification was significantly enhanced by treatment with glyc-LDL, but not by native LDL. Furthermore, we found that ALP activity was significantly elevated as early as day 4 in glyc-LDL treated cells, compared to those incubated in native LDL. The glyc-LDL-induced mineralisation was not attenuated in the presence of osteoprotegrin (OPG) nor in the presence of two novel small RAGE antagonist peptides, which were designed to prevent RAGE binding with several of its most important ligands, including HMGB-1, S100P and S1004A. Conclusion We have shown that human-derived glyc-LDL accelerates vascular calcification in vitro . This process does not appear to be attenuated by the addition of OPG, suggesting AGE-induced accelerated calcification occurs through a pathway independent of the RANKL/OPG signalling activity. Further studies with a range of RAGE inhibitors should allow the identification of the molecular pathways implicated in glyc-LDL induced calcification to enable the development of therapeutic peptides effective in blocking of RAGE-ligand interaction, which is prevalent in many pathologies.

Defects of either anosmin-1 or fibroblast growth factor receptor 1 (FGFR1) are known to underlie hereditary Kallmann's syndrome (KS), a human disorder of olfactory and gonadotropin-releasing hormone (GnRH) neuronal ontogeny. Here, we report a functional interaction between anosmin-1 and the FGFR1-FGF2-heparan sulfate complex, leading to amplified responses in the FGFR1 signaling pathway. In human embryonic GnRH olfactory neuroblasts, wild-type anosmin-1, but not proteins with loss-of-function KS mutations, induces neurite outgrowth and cytoskeletal rearrangements through FGFR1-dependent mechanisms involving p42/44 and p38 mitogen-activated protein kinases and Cdc42/Rac1 activation. Furthermore, anosmin-1 enhances FGF2 signaling specifically through FGFR1 IIIc in heterologous BaF3 lymphoid cells in a heparan sulfate-dependent manner. Our study provides compelling evidence for anosmin-1 as an isoform-specific co-ligand modulator of FGFR signaling that amplifies and specifies FGFR1 signaling responses during human nervous system development and defines a mechanism underlying the link between autosomal and X-linked KS.

The dose adjustment for normal eating (DAFNE) course for people with type 1 diabetes is an evidence based, structured education programme that provides them with the skills they need to estimate the carbohydrate content in each meal and inject the right dose of insulin. A total of 3387 DAFNE courses were delivered up to June 2012. The DAFNE course is delivered to small groups by trained diabetes specialist nurses and dietitians over five consecutive days. Participants are taught to match their insulin dose to their chosen food intake on a meal by meal basis. The DAFNE doctor programme enables doctors to provide leadership and clinical support to DAFNE educators in the delivery of DAFNE courses. Doctors who have completed the doctor programme can deliver the introduction and facilitate the question …