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OBJECTIVES Arterial stiffness has been proposed as a marker of arteriovenous fistula failure and can be measured locally by using ultrasound shear wave elastography (SWE). This preliminary study aimed to assess whether SWE measurements of the brachial artery were associated with arteriovenous fistula failure. METHODS Data were collected on patients who were indicated for fistula creation. Preoperative and postoperative vessel diameters from B-mode ultrasound, brachial artery SWE maps, and demographic data were collected. Logistic and linear regression analyses were used to determine whether any of these variables were related to the outcome of the fistula 3 months after creation. RESULTS Data were acquired for 33 patients. Shear wave velocity values decreased after fistula creation (mean ± SD, -1.2 ± 1 m/s; P

Aim We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. Methods and results We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference −1.37 (95% confidence interval: −2.63 to −0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. Conclusion Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.

Strain measurements by US have been suggested as a method of assessing arterial elasticity prior to arterio venous fistula creation. This pilot study sought to develop an imaging protocol to measure strain in the brachial artery via velocity vector imaging (VVI) and determine if differences in strain could be observed between a healthy group and a group with end-stage renal disease (ESRD), and if VVI measurements were associated with arterio-venous fistula malfunction. 40 healthy volunteers and 33 patients with ESRD were included in this study. All participants underwent US assessment of brachial artery strain via VVI. Peak velocity, strain, strain-rate and velocity were assessed. Patients with and without AVF failure at 3-months were assessed for differences in VVI measurement. Mean VVI measurements between the patient and volunteer groups were similar, and no significant differences were observed. Measurements were reproducible. No significant differences were observed in patients with or without AVF dysfunction. The results from this pilot study suggest VVI measurements of brachial artery mechanics are feasible and that VVI measurements may be used to assess age related changes of the brachial artery.

The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer's disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia, and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize the so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures of the enzymes from P.��gingivalis (PgQC) and T.��forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded ��-sheet surrounded by seven ��-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P.��gingivalis clinical isolates in a dose-dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases.

Background Texture analysis (TA) is a technique that measures the MRI signal via pixel greyscale variations (figure 1), and may be useful in cardiac MR (CMR) for detecting features not visible to the human eye. Purpose To use TA to examine myocardial CINE MR Images in a cohort of volunteers. Major feature differences were anticipated between images at end diastole (ED) and end systole (ES), whilst minor differences were anticipated between younger and older volunteers. Methods Two cohorts (each n=30) were studied - young (44±3 years), and old (68±4 years). A 2D ECG-gated breath-hold segmented steady-state gradient echo sequence was used. Myocardial TA features were derived using MaZda v4.7. Measurements were made by two observers. Results A total of 39 TA features were significantly different between ED and ES (p Conclusion Selected TA features in CINE CMR are repeatable and can identify differences between major and minor texture changes. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Medical Research Scotland, Guerbet Group

Grit, defined as passion and perseverance for long-term goals, predicts success in a number of social domains. The present two studies examined grit and its subscales, and how these relate to both adaptive and maladaptive personality traits pertaining to success. For Study 1, based on data from 249 participants, results indicated that grit was correlated positively with proactive personality, personal growth initiative, and competitiveness, and the perseverance subscale also was correlated positively with self- and other-oriented perfectionism. The findings of Study 1 led us to further explore the dark aspects of grit in Study 2: based on data from 222 participants, results indicated that grit was correlated negatively with Machiavellianism, hypercompetitiveness, and most forms of narcissism but positively correlated with adaptive grandiose narcissism. Collectively, results reveal grit to be a positive, adaptive trait but raise questions regarding the perfectionistic tendencies of gritty individuals and the unitary nature of the construct.

Study design Real time in vivo measurement of forces in the cervical spine of goats following anterior cervical discectomy and fusion (ACDF). Objective To measure interbody forces in the cervical spine during the time course of fusion following ACDF with plates of different stiffnesses. Summary of background data Following ACDF, the biomechanics of the arthrodesis is largely dictated by the plate. The properties of the plate prescribe the extent of load-sharing through the disc space versus the extent of stress-shielding. Load-sharing promotes interbody bone formation and stress-shielding can inhibit maturation of bone. However, these principles have never been validated in vivo. Measuring in vivo biomechanics of the cervical spine is critical to understanding the complex relationships between implant design, interbody loading, load-sharing, and the progression of fusion. Methods Anterior cervical plates of distinct bending stiffnesses were placed surgically following ACDF in goats. A validated custom force-sensing interbody implant was placed in the disc space to measure load-sharing in the spine. Interbody loads were measured in vivo in real time during the course of fusion for each plate. Results Interbody forces during flexion/extension were highly dynamic. In animals that received high stiffness plates, maximum forces were in extension whereas in animals that received lower stiffness plates, maximum forces were in flexion. As fusion progressed, interbody load magnitude decreased. Conclusion The magnitude of interbody forces in the cervical spine is dynamic and correlates to activity and posture of the head and neck. The magnitude and consistency of forces in the interbody space correlates to plate stiffness with more compliant plates resulting in more consistent load-sharing. The magnitude of interbody forces decreases as fusion matures suggesting that smart interbody implants may be used as a diagnostic tool to indicate the progression of interbody fusion. Level of evidence N/A.

Aim We tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with type 2 diabetes (T2D). Methods and results We randomly assigned 66 people (mean age 67 ± 7 years, 38 males) with T2D, LVH, and controlled blood pressure (BP) to receive dapagliflozin 10 mg once daily or placebo for 12 months. Primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging. In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo with an absolute mean change of −2.82g [95% confidence interval (CI): −5.13 to −0.51, P = 0.018]. Additional sensitivity analysis adjusting for baseline LVM, baseline BP, weight, and systolic BP change showed the LVM change to remain statistically significant (mean change −2.92g; 95% CI: −5.45 to −0.38, P = 0.025). Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h systolic BP (P = 0.012), nocturnal systolic BP (P = 0.017), body weight (P < 0.001), visceral adipose tissue (VAT) (P < 0.001), subcutaneous adipose tissue (SCAT) (P = 0.001), insulin resistance, Homeostatic Model Assessment of Insulin Resistance (P = 0.017), and high-sensitivity C-reactive protein (hsCRP) (P = 0.049). Conclusion Dapagliflozin treatment significantly reduced LVM in people with T2D and LVH. This reduction in LVM was accompanied by reductions in systolic BP, body weight, visceral and SCAT, insulin resistance, and hsCRP. The regression of LVM suggests dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to the cardio-protective effects of dapagliflozin. ClinicalTrials.gov Identifier NCT02956811

This review examines four imaging modalities; ultrasound (US), digital subtraction angiography (DSA), magnetic resonance imaging (MRI) and computed tomography (CT), that have common or potential applications in vascular access (VA). The four modalities are reviewed under their primary uses, techniques, advantages and disadvantages, and future directions that are specific to VA. Currently, US is the most commonly used modality in VA because it is cheaper (relative to other modalities), accessible, non-ionising, and does not require the use of contrast agents. DSA is predominantly only performed when an intervention is indicated. MRI is limited by its cost and the time required for image acquisition that mainly confines it to the realm of research where high resolution is required. CT’s short acquisition times and high resolution make it useful as a problem-solving tool in complex cases, although accessibility can be an issue. All four imaging modalities have advantages and disadvantages that limit their use in this particular patient cohort. Current imaging in VA comprises an integrated approach with each modality providing particular uses dependent on their capabilities. MRI and CT, which currently have limited use, may have increasingly important future roles in complex cases where detailed analysis is required.

This paper reviews applications of experimental modelling in vascular access for hemodialysis. Different techniques that are used in in-vitro experiments are bulk pressure and flow rate measurements, Laser Doppler Velocimetry and Vector Doppler Ultrasound point velocity measurements, and whole-field measurements such as Particle Image Velocimetry, Ultrasound Imaging Velocimetry, Colour Doppler Ultrasound, and Planar Laser Induced Fluorescence. Of these methods, the ultrasound techniques can also be used in-vivo, to provide realistic boundary conditions to in-vitro experiments or numerical simulations. In the reviewed work, experimental modelling is mainly used to support computational models, but also in some cases as a tool on its own. It is concluded that, to further advance the utility of computational modelling in vascular access research, a rigorous verification and validation procedure should be adopted. Experimental modelling can play an important role in both in-vitro validation, and the quantification of the accuracy, uncertainty, and reproducibility of in-vivo measurement methods.

Background: Porphyromonas gingivalis, a major pathogen associated with chronic periodontitis, secretes variety of proteins, majority of which begins with glutamine. Several of these proteins were found with pyroglutamate (pGlu) at N-terminus suggesting the presence of this posttranslational modification pathway in P.gingivalis. The observation that N-terminal glutamine is over-represented as the first amino acid after signal peptide cleavage, and subsequent confirmation of pGlu formation on the nascent protein via mass spectrometry, led us to conclude that an enzyme must be present as the executor of this reaction. Hypothesis: PG2157 is a glutaminyl cyclase and is responsible for the cyclization of N-terminal glutamine residues. Methods: A homology search was used to identify a gene (PG2157) encoding a protein homologous to human glutaminyl cyclase (QC) in the P. gingivalis genome. The gene was cloned, expressed in E. coli and recombinant PgQC purified. The protein was crystalized, and structure determined by molecular replacement. The rPgQC activity was characterized with respect to pH, ionic strength, optimum substrate specificity, and sensitivity to inhibition by an array of non-specific and specific inhibitors. Finally, subcellular localization of PgQC in P. gingivalis was determined. Results: PgQC specificity is restricted for N-terminal glutamine. The enzyme converts this residue to pGlu with kcat/Km at 1.34 s-1. The reaction was fastest at low ionic strength and at pH around 8.0. The activity was inhibited by o-phenanthroline (≥100µM) and EDTA (≥100mM EDTA). Cu2+ and Zn2+ at ≥100nM exerted ≥90% inhibition. The activity was also significantly affected by cysteamine, imidazole, and reduced glutathione. In bacterial cells PgQC was found associated with the inner membrane as a lipoprotein facing the periplasm. The crystalline structure of PgQC showed strong similarity to human QC on the atomic level. Nevertheless, an inhibitor specific for human QC had a limited effect on the PgQC activity. Conclusions: PgQC is an enzyme resembling mammalian QC and it is responsible for pyroglutamination of proteins secreted by the T9SS of P. gingivalis. This activity is likely essential for bacterium viability since all attempts to produce a viable PgQC knockout failed. Taking into account that also T. forsythia and P. intermedia possess similar enzymes and the frequency of the Q value of Bacteriodetes it is likely that similar post-translatonal modification plays a pivotal role in protein secretion by these periodontal pathogens. Therefore, inhibition of bacterial QC may represent a novel approach to treat periodontal diseases.

Background: Epicardial adipose tissue (EAT) is an emerging cardio-metabolic risk factor that has been shown to correlate with adverse cardiovascular outcomes through potential local and systemic effects. Consequently, EAT has been proposed as a therapeutic target. The biguanide, metformin, and Sodium-glucose Cotransporter-2 inhibitors have been reported to improve cardiovascular outcomes. We have investigated the effects of both metformin and dapagliflozin, on EAT in patients with prediabetes and type 2 diabetes respectively. Methods: EAT area measurements were performed blindly on cine 4 chamber views during the end diastolic phase of the cardiac cycle at baseline and at the end of study treatment using CMR scans in patients that participated in two randomized double-blinded placebo controlled trials: (1) MET-REMODEL (ClinicalTrials.gov. NCT02226510) (n=68 patients, mean age 65 ± 8 y; mean BMI 31.9 ± 3.6 kg/m²) with prediabetes and /or insulin resistance who received either metformin (2g /day) or placebo for 12 months and (2) REFORM (ClinicalTrial.gov NCT02397421) (n=56 patients, mean age 67 ± 7 y; mean BMI 32.5± 5.3 kg/m²) with chronic heart failure and type 2 diabetes who received either dapagliflozin (10mg/day) or placebo for 12 months respectively. Results: Metformin treatment in the METREMODEL trial reduced body weight significantly by 4.2kgs (p=0.001).but did not reduce EAT area (metformin -0.1 ± 3.8 cm² vs. placebo -0.5 ± 2.9 cm² p= 0.7). In the REFORM trial, dapagliflozin reduced body weight significantly by -1.9 kg (p= 0.054) with no significant reduction in EAT area (dapagliflozin -1.00 ± 3.6 cm² vs. placebo -0.7 ± 3.1 p=0.8). Conclusion: In prediabetes and type 2 diabetes, we found that metformin and dapagliflozin treatment resulted in significant weight loss but had no significant effect on EAT. Our findings suggest that the reported cardiovascular benefits of these two diabetic therapies are not likely to be mediated by effects on EAT. Disclosure S. Al-Talabany: None. J. Weir-McCall: None. M. Mohan: None. J.S. Singh: None. I. Mordi: None. S.J. Gandy: None. F. Khan: None. A. Choy: None. J.G. Houston: None. E. Pearson: Speaker's Bureau; Self; Eli Lilly and Company. J. George: None. A.D. Struthers: Research Support; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca. C.C. Lang: None.

Background: Left ventricular hypertrophy (LVH) is highly prevalent in patients with coronary artery disease (CAD) and is an independent predictor of cardiovascular mortality. Metformin has been shown to regress LV mass (LVM) in animal models of LVH. We hypothesize that metformin may regress LVH in nondiabetic and normotensive CAD patients with prediabetes and/or insulin resistance. Methods: In this randomized double-blind placebo controlled trial, 68 patients with prediabetes (HbA1c ?39 mmol/mol and less than 48 mmol/mol) and/or insulin resistance (fasting insulin resistance index ? 2.7) were assigned to receive either metformin (2g daily dose) or placebo for 12 months. An intention-to-treat (ITT) and per-protocol analysis was designed to determine the effect of metformin on the following study endpoints: Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging; other endpoints were changes in LVM, changes in body weight, office blood pressure (BP) and biomarkers. Results: In the ITT analysis (n=61), metformin treatment significantly reduced: LVMI (metformin -2.7 ± 2.3 g/m1.7 vs. placebo -1.4 ± 2.7 g/m1.7; P=0.05), body weight (lowered by 3.6 kgs, p=0.002), office systolic BP (metformin -4.8 ± 15.6 mmHg vs. placebo 4.6 ± 15.7 mmHg; P=0.02) and reduced concentration of thiobarbituric acid reactive substances (TBARs), a biomarker for oxidative stress (p=0.04). In the on-per protocol analysis (n=56), metformin resulted in a greater reduction of LVMI (metformin -3.1 ± 1.9 g/m1.7 vs. placebo -1.2 ± 2.7 g/m1.7; P=0.005), and greater weight reduction of 4.2kgs (p=0.001). Conclusions: Metformin treatment significantly reduced LVMI, office SBP, body weight and oxidative stress. These results reveal a novel mechanism for the cardioprotective effect of metformin and raise the possibility of using metformin in nondiabetic patients with CAD. Disclosure M. Mohan: None. S. Al-Talabany: None. A.M. McKinnie: None. I. Mordi: None. J.S. Singh: None. S.J. Gandy: None. A. Choy: None. J.G. Houston: None. J. George: None. A.D. Struthers: Research Support; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca. C.C. Lang: None.

Introduction: DM and heart failure (HF) are lethal, with limited diabetic therapy options. Sodium-glucose linked transporter 2 (SGLT2) inhibitors have been reported to have CV benefits in at risk DM patients. We are the first to study the CV effects of SGLT2 inhibition in patients with DM and HF. Methods: In this randomized double-blind placebo controlled trial, 56 patients (mean age: 67.1 years, males: 66%) with DM and echocardiographically confirmed HF with reduced ejection fraction (HFrEF) on regular diuretic therapy were assigned to dapagliflozin 10mg OD or placebo for one year. Primary endpoint was the difference in left ventricular (LV) volumes between both groups using cardiac MRI. Secondary endpoints include LV mass, LV ejection fraction (EF), weight, BP and diuretic use. Outcomes were analysed using linear regression controlling for baseline values, age, sex and renal function. Results: There was no difference between dapagliflozin and placebo in the primary endpoints of LV end diastolic volume (LVEDV) or LV end systolic volume (LVESV); +4.71mls; 95% CI: -17.to 26.50 and +1.52mls; 95% CI: -15.68 to 18.72 respectively. However, when an interaction term for starting LVEF was added to the model, dapagliflozin significantly lowered LVEDV, LVESV and LV mass in those with starting LVEF ≥ 45%; -15.59mls; p=0.019, -15.20mls; p=0.016 and -4.87gm/m2; p=0.026. Patients on dapagliflozin had weight reduction; -1.90kg; 95% CI: -3.83 to +0.04; p=0.054, lower diastolic BP; -6.34mmHg; 95% CI: -11.35 to -1.32; p=0.014 and higher hemoglobin; +1.23 g/dl; 95% CI: 0.65 to 1.82; p Conclusions: Our data show dapagliflozin treatment resulted in weight and blood pressure reduction among patients with DM and HFrEF. There was evidence to suggest that dapagliflozin may cause LV reverse remodelling in DM patients with mild, but not with more severe HFrEF. Disclosure J.S.S. Singh: None.I. Mordi: None.M. Mohan: None.S.J. Gandy: None. E. Pearson: Speaker's Bureau; Self; Eli Lilly and Company.J.G. Houston: None. A.D. Struthers: Research Support; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca.C.C. Lang: None.

Objectives To compare aortic size and stiffness parameters on MRI between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients with aortic stenosis (AS). Methods MRI was performed in 174 patients with asymptomatic moderate-severe AS (mean AVAI 0.57 ± 0.14 cm2/m2) and 23 controls on 3T scanners. Valve morphology was available/analysable in 169 patients: 63 BAV (41 type-I, 22 type-II) and 106 TAV. Aortic cross-sectional areas were measured at the level of the pulmonary artery bifurcation. The ascending and descending aorta (AA, DA) distensibility, and pulse wave velocity (PWV) around the aortic arch were calculated. Results The AA and DA areas were lower in the controls, with no difference in DA distensibility or PWV, but slightly lower AA distensibility than in the patient group. With increasing age, there was a decrease in distensibility and an increase in PWV. After correcting for age, the AA maximum cross-sectional area was higher in bicuspid vs. tricuspid patients (12.97 [11.10, 15.59] vs. 10.06 [8.57, 12.04] cm2, p

To compare non-contrast enhanced MRI with ultrasound (US) for measurement of arm blood vessel geometries and flow velocities in volunteers and patients with end-stage renal disease.Subjects were scanned using US (reference standard), and MRI 2D time-of-flight (ToF), 2D phase contrast (PC), and 3D multi-echo data image combination (MEDIC). Patients were also scanned after arteriovenous fistula (AVF) surgery.For mean vessel diameters (radial and brachial arteries; cephalic vein) MEDIC measurements were similar to US (p 0.05). However, ToF underestimated the mean diameter of the cephalic vein relative to US (p 0.05). For arterial velocity measurements, the mean values derived by PC-MR and US were similar (p 0.05). Post-operatively, the intra-luminal signal intensity was hypo-intense at the anastomosis site using ToF and MEDIC. At the same site the outer boundary of the vessel was consistently lost on ToF, but remained clearly delineated on the MEDIC images.With the exception of ToF, the MRI data demonstrated excellent agreement with US for measurements of vessel geometry and flow velocity. Further, the ability to clearly delineate the post-surgery vessel edges with MEDIC MRI suggests that the technique may be useful for surveillance after AVF creation or for patient-specific modelling studies.

Gingipain proteases are important virulence factors from the periodontal pathogen Porphyromonas gingivalis and are the target of many in vitro studies. Due to their close biochemical properties, purification of individual gingipains is difficult and requires multiple chromatographic steps. In this study, we demonstrate that insertion of a hexahistidine affinity tag upstream of a C-terminal outer membrane translocation signal in RgpB gingipain leads to the secretion of a soluble, mature form of RgpB bearing the affinity tag that can easily be purified by nickel-chelating affinity chromatography. The final product obtained high yielding high purity is biochemically indistinguishable from the native RgpB enzyme.

Vascular disease, whether it be atherosclerosis, inflammatory, or hereditary vasculitide, is a systemic disorder with disease in one territory predictive of disease in another. Despite this, current approaches focus on single-territory assessment ignoring the global burden of disease. Advances in MRI have enabled us to surmount previous limitations and expand our approach to such conditions with the ability to simultaneously assess the entirety of the arterial tree in a single examination, allowing a staging examination as it were, of the vascular health in its totality. This review will cover the acquisition technique, reporting, clinical utility, and current evidence base for such an approach.

Surveys of 1217 undergraduate students supported the reliability (inter-item and test-retest) and validity of the Prosocial and Aggressive Driving Inventory (PADI). Principal component analyses on the PADI items yielded two scales: Prosocial Driving (17 items) and Aggressive Driving (12 items). Prosocial Driving was associated with fewer reported traffic accidents and violations, with participants who were older and female, and with lower Boredom Susceptibility and Hostility scores, and higher scores on Agreeableness, Conscientiousness, Openness, and Neuroticism. Aggressive Driving was associated with more frequent traffic violations, with female participants, and with higher scores on Competitiveness, Sensation Seeking, Hostility, and Extraversion, and lower scores on Conscientiousness, Agreeableness, and Openness. The theoretical and practical implications of the PADI's dual focus on safe and unsafe driving are discussed.

Objectives This study sought to ascertain whether high-dose allopurinol causes regression of left ventricular mass (LVM) in patients with type 2 diabetes mellitus (T2DM). Background Left ventricular hypertrophy (LVH) is common in T2DM and contributes to patients9 high cardiovascular (CV) event rate. Oxidative stress (OS) has been implicated in LVH development, and allopurinol has been previously shown to reduce vascular OS. We therefore investigated whether allopurinol causes regression of LVH in patients with T2DM. Methods We conducted a randomized, double-blind, placebo-controlled study of 66 optimally-treated T2DM patients with echocardiographic evidence of LVH. Allopurinol, 600 mg/day, or placebo was given over the study period of 9 months. The primary outcome was reduction in LVM as calculated by cardiac magnetic resonance imaging at baseline and at 9 months9 follow-up. Secondary endpoints were change in flow-mediated dilation and augmentation index. Results Allopurinol significantly reduced absolute LVM (−2.65 ± 5.91 g vs. placebo group +1.21 ± 5.10 g [p = 0.012]) and LVM indexed to body surface area (−1.32 ± 2.84 g/m2 vs. placebo group +0.65 ± 3.07 g/m2 [p = 0.017]). No significant changes were seen in either flow-mediated dilation or augmentation index. Conclusions Allopurinol causes regression of LVM in patients with T2DM and LVH. Regression of LVH has been shown previously to improve CV mortality and morbidity. Therefore, allopurinol therapy may become useful to reduce CV events in T2DM patients with LVH. (Allopurinol in Patients with Diabetes and LVH; UKCRN 8766)

This study examined the relationship between trait competitiveness and occupational interests of under-graduates prior to entering the work force. The findings indicate that competitiveness is related to Investigative and Realistic types within Holland’s model of vocational choice and that competitive individuals are attracted to jobs involving competition and competitive pressure based on O*NET job characteristic ratings. Implications for future research are discussed.

SummaryObjective The significant role of corticosteroids in hypertension and cardiovascular disease highlights the importance of the adrenal gland in these disorders. The ability to correlate corticosteroid production with adrenal volume offers a novel research tool and intermediate phenotype in cardiovascular disease. The aim of this study was to develop and validate the use of magnetic resonance imaging (MRI) in adrenal volume assessment and investigate whether this associates with corticosteroid production. Design/Methods Twenty normotensive men underwent noncontrast 1·5T MRI scanning of adrenals, measurement of blood pressure and plasma corticosteroids. Left adrenal volume was calculated twice using standard segmentation software by four independent observers with differing levels of clinical expertise and segmentation experience. To optimize this process, adrenal ‘phantoms’ with known fixed volumes underwent MRI scanning and analysis by two observers. Results Intra-observer coefficients of repeatability (CoRs) in phantoms ranged from 0·23 to 0·43 ml (interobserver CoR 0·48 ml). In the subject group, mean adrenal volumes were 3·99–5·82 ml with intra-observer CoRs 0·27–1·94 ml. Interobserver variability was 2·73 ml. Segmentation expertise was the main factor affecting variability, with experienced observers having the lowest CoRs; clinical knowledge was a factor when combined with segmentation experience. Mean adrenal volume correlated with plasma glucocorticoids (r = 0·523, P

et al., [Background]: Arginine-specific (RgpB and RgpA) and lysine-specific (Kgp) gingipains are secretory cysteine proteinases of Porphyromonas gingivalis that act as important virulence factors for the organism. They are translated as zymogens with both N- and C-terminal extensions, which are proteolytically cleaved during secretion. In this report, we describe and characterize inhibition of the gingipains by their N-terminal prodomains to maintain latency during their export through the cellular compartments. [Methods]: Recombinant forms of various prodomains (PD) were analyzed for their interaction with mature gingipains. The kinetics of their inhibition of proteolytic activity along with the formation of stable inhibitory complexes with native gingipains was studied by gel filtration, native PAGE and substrate hydrolysis. [Results]: PD RgpB and PDRgpA formed tight complexes with arginine-specific gingipains (Ki in the range from 6.2 nM to 0.85 nM). In contrast, PDKgp showed no inhibitory activity. A conserved Arg-102 residue in PDRgpB and PDRgpA was recognized as the P1 residue. Mutation of Arg-102 to Lys reduced inhibitory potency of PD RgpB by one order of magnitude while its substitutions with Ala, Gln or Gly totally abolished the PD inhibitory activity. Covalent modification of the catalytic cysteine with tosyl-l-Lys-chloromethylketone (TLCK) or H-D-Phe-Arg-chloromethylketone did not affect formation of the stable complex. [Conclusion]: Latency of arginine-specific progingipains is efficiently exerted by N-terminal prodomains thus protecting the periplasm from potentially damaging effect of prematurely activated gingipains. General significance Blocking progingipain activation may offer an attractive strategy to attenuate P. gingivalis pathogenicity. © 2013 Elsevier B.V., This study was supported in part by grants from European, US American, Polish, Spanish, and Catalan agencies (UMO-2012/04/A/NZ1/00051, 2011/03/N/NZ1/00586, 2137/7.PR-EU/2011/2, DE09761, FP7-HEALTH-F3-2009-223101 “AntiPathoGN”; FP7-HEALTH-2010-261460 “Gums&Joints”; FP7-PEOPLE-2011-ITN-290246 “RAPID”; BIO2009-10334; BFU2012-32862; CSD2006-00015; Fundació “La Marató de TV3” grant 2009-100732; and 2009SGR1036).

Iñaki de Diego et al., In the recently characterized Type IX Secretion System (T9SS), the conserved C-terminal domain (CTD) in secreted proteins functions as an outer membrane translocation signal for export of virulence factors to the cell surface in the Gram-negative Bacteroidetes phylum. In the periodontal pathogen Porphyromonas gingivalis, the CTD is cleaved off by PorU sortase in a sequence-independent manner, and anionic lipopolysaccharide (A-LPS) is attached to many translocated proteins, thus anchoring them to the bacterial surface. Here, we solved the atomic structure of the CTD of gingipain B (RgpB) from P. gingivalis, alone and together with a preceding immunoglobulin-superfamily domain (IgSF). The CTD was found to possess a typical Ig-like fold encompassing seven antiparallel β-strands organized in two β-sheets, packed into a β-sandwich structure that can spontaneously dimerise through C-terminal strand swapping. Small angle X-ray scattering (SAXS) revealed no fixed orientation of the CTD with respect to the IgSF. By introducing insertion or substitution of residues within the inter-domain linker in the native protein, we were able to show that despite the region being unstructured, it nevertheless is resistant to general proteolysis. These data suggest structural motifs located in the two adjacent Ig-like domains dictate the processing of CTDs by the T9SS secretion pathway., This study was financially supported in part by grants from European, US American, Polish, Spanish, and Catalan agencies (UMO-2012/04/A/NZ1/00051, UMO-2012/05/B/NZ6/00581, UMO-2013/08/W/NZ1/00696, UMO-2011/01/D/NZ1/01169, 2975/7.PR/13/2014/2, NIH NIDCR DE09761; FP7-PEOPLE-2011-ITN-290246 “RAPID”; FP7-HEALTH-2012-306029-2 “TRIGGER”; BFU2012-32862; BIO2013-49320-EXP; MDM-2014-0435; 1306/MOB/IV/2015/0 (“Mobilność Plus” MK) and 2014SGR9). The Department of Structural Biology of IBMB is a “María de Maeztu” Unit of Excellence from the Ministry of Economy and Competitiveness. Funding for data collection was provided in part by ESRF

Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.

OBJECTIVE Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population. METHOD The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure. RESULTS The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found. CONCLUSIONS Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups.

This study investigated the theoretical and empirical links between narcissism and competitiveness by focusing on the multifaceted features of these individual difference variables. The present study compared measures of overt narcissism (Narcissistic Personality Inventory, NPI; Raskin & Terry, 1988) and covert narcissism (Hypersensitive Narcissism Scale, HSNS; Hendin & Cheek, 1997) with measures of competitiveness (Revised Competitiveness Index, CI-R; Houston, Harris, McIntire, & Francis, 2002) and hypercompetitiveness (Hypercompetitive Attitude Scale, HCS; Ryckman, Hammer, Kaczor, & Gold, 1990). Based on a sample of 324 undergraduates, positive relationships were found between overt narcissism and general competitiveness and hypercompetitiveness. However, covert narcissism was negatively related to general competitiveness but positively related to hypercompetitiveness. The findings highlight the similarities and distinctions between different forms of narcissism and competitiveness and provide a broader framework for understanding the relationship between narcissism and competitiveness. Implications for the interpersonal manifestation of these different forms are discussed.

Patients with nonpsychotic mental health and emotional problems are commonly seen by primary care physicians. The objective of this study was to expand the Provisional Diagnostic Instrument-4 (PDI-4) to include a short self-report screen for 5 common anxiety-related diagnoses: panic attack (PA), social phobia (SP), obsessive-compulsive disorder (OCD), hypochondriasis, and post-traumatic stress disorder (PTSD). Primary care patients (N = 343) were originally evaluated with a self-report screen comprised of 85 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition symptom-based candidate questions, then interviewed by a trained rater for Structured Clinical Interview Research Version (SCID)/Adult ADHD Clinician Diagnostic Scale version 1.2 (ACDS) assessment and diagnosis. Responses to screening questions were used to calculate sensitivity and specificity for an SCID diagnosis, and to select the optimal cutoffs in symptom frequency for 1 or 2 questions for each additional anxiety-related diagnosis. The PDI-4 Anxiety (PDI-4A) contains 6 items for provisional differential diagnosis of PA, SP, OCD, hypochondriasis, and PTSD in addition to items for the PDI-4. Sensitivities/specificities were: PA, 88%/68%; SP, 57%/70%; OCD, 88%/61%; hypochondriasis, 67%/85%; and PTSD, 71%/72%. Screening for multiple common anxiety diagnoses may be desirable, although limitations may include reduced sensitivity and specificity for selected diagnoses. The PDI-4A may additionally help primary care physicians identify patients with PA, SP, OCD, hypochondriasis, and PTSD.

Potential predictors of remission in mixed bipolar I disorder were identified using early Clinical Global Impression-Severity (CGI-S) improvement criteria in divalproex-resistant patients randomized to olanzapine augmentation (olanzapine + divalproex; N = 101) in a 6-week, double-blind, placebo-controlled trial. In a post-hoc analysis, receiver operating characteristics of 1-point decreases in the CGI-S total score after 2, 4, 7, and 14 days were examined as predictors of endpoint (Week 6 or last observation) remission of depression and/or mania as defined by 21-item Hamilton Depression Rating Scale (HDRS-21) and Young Mania Rating Scale (YMRS) total score ≤8. Based on a 1-point improvement in CGI-S as a predictor of remission, all odds ratios (ORs) and 95% confidence intervals (CIs) were statistically significant for depression or mania remission criteria. ORs for mixed symptom remission with a decrease ≥1 in CGI-S scores at Day 2 for olanzapine augmentation were (6.727; CI: 2.382, 18.997; p < .001) with negative predictive value = 89.5% and positive predictive value = 44.2%. Changes in HDRS-21 and YMRS individual item scores after 2 days of augmentation as predictors of endpoint remission identified that decreases in HDRS-21 symptom item scores (early, middle, and/or late insomnia; paranoid; agitation; and somatic/gastrointestinal) predicted depressive symptom remission at endpoint, and decreases in YMRS item scores (language-thought disorder and irritability) were associated with manic symptom remission at endpoint. Because remission with augmentation therapy may occur in as few as one in ten individuals who lack very early symptom reduction, lack of early improvement may indicate a need to expediently reassess treatment strategy.

Objective To evaluate common genetic variations for association with symptomatic improvement in bipolar I depression following treatment with olanzapine/fluoxetine combination (OFC) or lamotrigine. Method Symptom improvement was assessed in 88 OFC-treated and 85 lamotrigine-treated white patients with bipolar I depression in the 7-week acute period of a randomized, double-blind study comparing OFC (6/25, 6/50, 12/25, or 12/50 mg/d [olanzapine/fluoxetine]) with lamotrigine (titrated to 200 mg/d). The original study was conducted from November 2003 to August 2004. Single nucleotide polymorphisms (SNPs) were genotyped in a set of 19 candidate genes corresponding to known sites of activity for olanzapine and fluoxetine or previously associated with antidepressant or antipsychotic response. Primary outcome was the reduction in Montgomery-Asberg Depression Rating Scale (MADRS) total score as assessed by the difference by genotype from baseline to week 7 from a mixed-effects repeated measures analysis with terms for visit, genotype, genotype-by-visit interaction, and baseline MADRS score as a covariate. Results SNPs within the dopamine D(3) receptor and histamine H(1) receptor (HRH1) genes were significantly associated with response to OFC. SNPs within the dopamine D(2) receptor, HRH1, dopamine beta-hydroxylase, glucocorticoid receptor, and melanocortin 2 receptor genes were significantly associated with response to lamotrigine. Conclusions SNPs in specific candidate genes were associated with symptomatic improvement in a treatment-specific fashion. These results suggest the importance of dopaminergic effects in the treatment of patients with bipolar I depression and the potential utility of genotyping in selection of pharmacologic treatments for bipolar depression.

The study's goal was to characterize the typology of patient outcomes based on social and occupational functioning and psychiatric symptoms following antipsychotic drug treatment, and to explore predictors of group membership representing the best/worst outcomes. A hierarchical cluster analysis was used to define groups of patients (n=1449) based on endpoint values for psychiatric symptoms, social functioning, and useful work measured up to 30 weeks of treatment. Stepwise logistic regression was used to construct predictive models of cluster membership for baseline predictors, and with 2/4/8 weeks of treatment. Five distinct clusters of patients were identified at endpoint (Clusters A-E). Patients in Cluster A (25.6%, best outcome) had minimal psychiatric symptoms and mild functional impairment, while patients in Cluster D (14.3%) and E (14.8%) (worst outcome) had moderate-to-severe symptoms and severe functional impairment. Occupational functioning, disorganized thinking, and positive symptoms were sufficient to describe the clusters. Membership in the best/worst clusters was predicted by baseline scores for functioning and symptom severity, and by early changes in symptoms with treatment. Psychiatric symptoms and functioning provided complementary information to describe treatment outcomes. Early symptom response significantly improved the prediction of outcome, suggesting that early monitoring of treatment response may be useful in clinical practice.