Assessment of coronary artery disease and calcified coronary plaque burden by computed tomography in patients with and without diabetes mellitus

Purpose

To compare the coronary atherosclerotic burden in patients with and without type-2 diabetes using CT Coronary Angiography (CTCA).

Methods and Materials

147 diabetic (mean age: 65?±?10?years; male: 89) and 979 nondiabetic patients (mean age: 61?±?13?years; male: 567) without a history of coronary artery disease (CAD) underwent CTCA. The per-patient number of diseased coronary segments was determined and each diseased segment was classified as showing obstructive lesion (luminal narrowing >50%) or not. Coronary calcium scoring (CCS) was assessed too.

Results

Diabetics showed a higher number of diseased segments (4.1?±?4.2 vs. 2.1?±?3.0; p??400 (p?p?p?p?=?0.003) and obstructive CAD (12.5% vs. 3.8%, p?=?0.01). Among patients with CCS????10 all diabetics with obstructive CAD had a zero CCS and one patient was asymptomatic.

Conclusions

Diabetes was associated with higher coronary plaque burden. The present study demonstrates that the absence of coronary calcification does not exclude obstructive CAD especially in diabetics.     

Metabolic–dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson’s disease

Purpose The unilateral 6-hydroxydopamine (6-OHDA) lesion rat model is a well-known acute model for Parkinson’s disease (PD). Its validity has been supported by invasive histology, behavioral studies and electrophysiology. Here, we have characterized this model in vivo by multitracer imaging [glucose metabolism and dopamine transporter (DAT)] in relation to behavioral and histological parameters. Methods Eighteen female adult Wistar rats (eight 6-OHDA-lesioned, ten controls) were investigated using multitracer [¹⁸F]-fluoro-2-deoxy-D-glucose (FDG) and [¹⁸F]-FECT {2′-[¹⁸F]-fluoroethyl-(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo(3.2.1)-octane-2-carboxylate} small animal positron emission tomography (PET). Relative glucose metabolism and parametric DAT binding images were anatomically standardized to Paxinos space and analyzed on a voxel-basis using SPM2, supplemented by a template-based predefined volumes-of-interest approach. Behavior was characterized by the limb-use asymmetry test; dopaminergic innervation was validated by in vitro tyrosine hydroxylase staining. Results In the 6-OHDA model, significant glucose hypometabolism is present in the ipsilateral sensory-motor cortex (−6.3%; p = 4 × 10⁻⁶). DAT binding was severely decreased in the ipsilateral caudate-putamen, nucleus accumbens and substantia nigra (all p < 5 × 10⁻⁹), as confirmed by the behavioral and histological outcomes. Correlation analysis revealed a positive relationship between the degree of DAT impairment and the change in glucose metabolism in the ipsilateral hippocampus (p = 3 × 10⁻⁵), while cerebellar glucose metabolism was inversely correlated to the level of DAT impairment (p < 3 × 10⁻⁴). Conclusions In vivo cerebral mapping of 6-OHDA-lesioned rats using [¹⁸F]-FDG and [¹⁸F]-FECT small animal PET shows molecular–functional correspondence to the cortico-subcortical network impairments observed in PD patients. This provides a further molecular validation supporting the validity of the 6-OHDA lesion model to mimic multiple aspects of human PD.     

Comprehensive analysis of six years experience in tubularised incised plate urethroplasty and its extended application in primary and secondary hypospadias repair

OBJECTIVE: We evaluated the potential of tubularised incised plate (TIP) urethroplasty in primary and secondary hypospadias repair focusing on the extended application of this procedure, the utility and handling of the urethral plate and operative results. METHODS: In this retrospective study, we analysed the medical records of 228 children with different levels of the hypospadiac meatus who underwent a TIP procedure between February 1997 and December 2002. The children were followed a mean of 42 months. Our medical records provided us with details about the location of the hypospadiac meatus, the width of the urethral plate before and after midline incision, primary versus secondary surgery, complications as well as notes on the extended application of the TIP procedure. RESULTS: The overall postoperative complication rate was 7.8%. The overall fistula rate was 5.7%, with 4.1% in primary distal, 9.6% in primary proximal and 7.5% in secondary repair respectively. We had one case of meatal stenosis (0.4%) and one of urethral stricture (0.4%) and 3 cases of glandular dehiscence (1.3%). Due to the encouraging results, the frequency of TIP procedure in hypospadias surgery increased from 33% in 1997 to 82% in 2002. CONCLUSION: In our study the TIP procedure has emerged as the first-choice technique in primary hypospadias repair--irrespective of the level of the hypospadiac meatus and the width of the original urethral plate. This procedure has also proved to be favourable for many cases at secondary surgery.     

Paediatric population neuroimaging and the Generation R Study: the second wave

Paediatric population neuroimaging is an emerging field that falls at the intersection between developmental neuroscience and epidemiology. A key feature of population neuroimaging studies involves large-scale recruitment that is representative of the general population. One successful approach for population neuroimaging is to embed neuroimaging studies within large epidemiological cohorts. The Generation R Study is a large, prospective population-based birth-cohort in which nearly 10,000 pregnant mothers were recruited between 2002 and 2006 with repeated measurements in the children and their parents over time. Magnetic resonance imaging was included in 2009 with the scanning of 1070 6-to-9-year-old children. The second neuroimaging wave was initiated in April 2013 with a total of 4245 visiting the MRI suite and 4087 9-to-11-year-old children being scanned. The sequences included high-resolution structural MRI, 35-direction diffusion weighted imaging, and a 6 min and 2 s resting-state functional MRI scan. The goal of this paper is to provide an overview of the imaging protocol and the overlap between the neuroimaging data and metadata. We conclude by providing a brief overview of results from our first wave of neuroimaging, which highlights a diverse array of questions that can be addressed by merging the fields of developmental neuroscience and epidemiology.     

Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin

The aim of this study was to develop a population pharmacokinetic model for interspecies allometric scaling of pegylated r-HuEPO (PEG-EPO) pharmacokinetics to man. A total of 927 serum concentrations from 193 rats, 6 rabbits, 34 monkeys, and 9 dogs obtained after a single dose of PEG-EPO, administered by the i.v. (dose range: 12.5–550 μg/kg) and s.c. (dose range: 12.5–500 μg/kg) routes, were pooled in this analysis. An open two-compartment model with first-order absorption and lag time (Tlag) and linear elimination from the central compartment was fitted to the data using the NONMEM V software. Body weight (WT) was used as a scaling factor and the effect of brain weight (BW), sex, and pregnancy status on the pharmacokinetic parameters was investigated. The final model was evaluated by means of a non-parametric bootstrap analysis and used to predict the PEG-EPO pharmacokinetic parameters in healthy male subjects. The systemic clearance (CL) in males was estimated to be 4.08WT1.030 × BW−0.345 ml/h. In females, the CL was 90.7% of the CL in males. The volumes of the central (Vc) and the peripheral (Vp) compartment were characterized as 57.8WT0.959 ml, and 48.1WT1.150 ml, respectively. Intercompartmental flow was estimated at 2.32WT0.930 ml/h. Absorption rate constant (Ka) was estimated at 0.0538WT−0.149. The absolute s.c. bioavailability F was calculated at 52.5, 80.2, and 49.4% in rat, monkey, and dog, respectively. The interindividual variability in the population pharmacokinetic parameters was fairly low (<35%). Non-parametric bootstrap confirmed the accuracy of the NONMEM estimates. The mean model predicted pharmacokinetic parameters in healthy male subjects of 70 kg were estimated at: CL: 26.2 ml/h; Vc: 3.6 l; Q: 286 l/h; Vp: 6.9 l, and Ka: 0.031 h⁻¹. The population pharmacokinetic model developed was appropriate to describe the time course of PEG-EPO serum concentrations and their variability in different species. The model predicted pharmacokinetics of PEG-EPO in humans suggest a less frequent dosing regimen relative to erythropoietin and darbepoetin, potentially leading to a simplification of anemia management.     

Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors

Herein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor β-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis a cluster of compounds was identified, which was based on a central pyrrole-2,4-1H-dicarboxamide scaffold, showing remarkable kinome selectivity. A scaffold-hop to the corresponding imidazole resulted in increased biochemical potency. Next, X-ray crystallography revealed a distinct binding mode compared to other TAK1 inhibitors. A benzylamide was found in a perpendicular orientation with respect to the core hinge-binding imidazole. Additionally, an unusual amide flip was observed in the kinase hinge region. Using structure-based drug design (SBDD), key substitutions at the pyrrolidine amide and the glycine resulted in a significant increase in biochemical potency.     

Moxifloxacin dosing in post-bariatric surgery patients

Introduction

Given the ever increasing number of obese patients and obesity related bypass surgery, dosing recommendations in the post-bypass population are needed. Using a population pharmacokinetic (PK) analysis and PK–pharmacodynamic (PD) simulations, we investigated whether adequate moxifloxacin concentrations are achieved in this population.

Methods

In this modelling and simulation study we used data from a trial on moxifloxacin PK. In this trial, volunteers who had previously undergone bariatric surgery (at least 6 months prior to inclusion), received two doses (intravenous and oral) of 400 mg moxifloxacin administered on two occasions.

Results

In contrast to other papers, we found that moxifloxacin PK were best described by a three compartmental model using lean body mass (LBM) as a predictor for moxifloxacin clearance. Furthermore, we showed that the probability of target attainment for bacterial eradication against a hypothetical Streptococcus pneumoniae infection is compromised in patients with higher LBM, especially when targeting microorganisms with minimum inhibitory concentrations (MICs) of 0.5 mg l⁻¹ or higher (probability of target attainment (PTA) approaching zero). When considering the targets for suppression of bacterial resistance formation, even at MIC values as low as 0.25 mg l⁻¹, standard moxifloxacin dosing does not attain adequate levels in this population. Furthermore, for patients with a LBM of 78 kg or higher, the probability of hitting this target approaches zero.

Conclusions

Throughout our PK–PD simulation study, it became apparent that, whenever optimal bacterial resistance suppression is deemed necessary, the standard moxifloxacin dosing will not be sufficient. Furthermore, our study emphasizes the need for a LBM based individualized dosing of moxifloxacin in this patient population.     

Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis

Introduction: Formation and enlargement of a necrotic core play a pivotal role in atherogenesis. Since the discovery of necroptosis, which is a regulated form of necrosis, prevention of necrotic cell death has become an attractive therapeutic goal to reduce plaque formation.

Areas covered: This review highlights the triggers and consequences of (unregulated) necrosis and necroptosis in atherosclerosis. The authors discuss different pharmacological strategies to inhibit necrotic cell death in advanced atherosclerotic plaques.

Expert opinion: Addition of a necrosis or necroptosis inhibitor to standard statin therapy could be a promising strategy for primary prevention of cardiovascular disease. However, a necrosis inhibitor cannot block all necrosis stimuli in atherosclerotic plaques. A necroptosis inhibitor could be more effective, because necroptosis is mediated by specific proteins, termed receptor-interacting serine/threonine-protein kinases (RIPK) and mixed lineage kinase domain-like pseudokinase (MLKL). Currently, only RIPK1 inhibitors have been successfully used in atherosclerotic mouse models to inhibit necroptosis. However, because RIPK1 is involved in both necroptosis and apoptosis, and also RIPK1-independent necroptosis can occur, we feel that targeting RIPK3 and MLKL could be a more attractive therapeutic approach to inhibit necroptosis. Therefore, future challenges will consist of developing RIPK3 and MLKL inhibitors applicable in both preclinical and clinical settings.     

Effectiveness of pharmaceutical care for patients with chronic obstructive pulmonary disease (PHARMACOP): a randomized controlled trial

AIMS

Few well-designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD.

METHODS

The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single-blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥50 years and with a smoking history of ≥10 pack-years. A computer-generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol-defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow-up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD-specific and generic health status and smoking behaviour.

RESULTS

From December 2010 to April 2011, 734 patients were enrolled. Forty-two patients (5.7%) were lost to follow-up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8–16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63–12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12–0.64; P = 0.003). No other significant between-group differences were observed.

CONCLUSIONS

Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.     

A note on sufficiency in binary panel models

Consider estimating the slope coefficients of a fixed‐effect binary‐choice model from two‐period panel data. Two approaches to semiparametric estimation at the regular parametric rate have been proposed: one is based on a sufficiency requirement, and the other is based on a conditional‐median restriction. We show that, under standard assumptions, both conditions are equivalent.