Molecular imaging of matrix metalloproteinases in atherosclerotic plaques.

Ischaemic stroke and myocardial infarction often result from the sudden rupture of an atherosclerotic plaque. The subsequent arterial thrombosis occluding the vessel lumen has been widely indicated as the crucial acute event causing peripheral tissue ischaemia. A complex cross-talk between systemic and intraplaque inflammatory mediators has been shown to regulate maturation, remodeling and final rupture of an atherosclerotic plaque. Matrix metalloproteinases (MMPs) are proteolytic enzymes (released by several cell subsets within atherosclerotic plaques), which favour atherogenesis and increase plaque vulnerability. Thus, the assessment of intraplaque levels and activity of MMP might be of pivotal relevance in the evaluation of the risk of rupture. New imaging approaches, focused on the visualisation of inflammation in the vessel wall and plaque, may emerge as tools for individualised risk assessment and prevention of events. In this review, we summarize experimental findings of the currently available invasive and noninvasive imaging techniques, used to detect the presence and activity of MMPs in atherosclerotic plaques.

Recovery of paraplegia after type B dissection due to spinal collateral recruitment.

Acute paraplegia could be a symptom of aortic dissection due to sudden compromise of arterial spinal cord blood supply. Complete spontaneous neurologic recovery is possible and was observed in the present case 3 hours after symptom onset. Spontaneous spinal cord reperfusion after acute type B dissection was probably due to two main mechanisms. Reperfusion of false lumen and collateral vascular network recruitment, recently confirmed by anatomic animal studies, serve as potential explanations. Favorable evolution of acute paraplegia after aortic dissection exists, but prognosis is uncertain, probably due to individual variable anatomic distribution of spinal cord blood supply.

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Novel calmodulin mutations associated with congenital arrhythmia susceptibility.

BACKGROUND: Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations. METHODS AND RESULTS: We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity. CONCLUSIONS: CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.

A Heterozygous Deletion Mutation in the Cardiac Sodium Channel Gene SCN5A with Loss- and Gain-of-Function Characteristics Manifests as Isolated Conduction Disease, without Signs of Brugada or Long QT Syndrome.

BACKGROUND: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome. METHOD AND RESULTS: In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation). CONCLUSION: In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.

The nNOS-p38MAPK Pathway Is Mediated by NOS1AP during Neuronal Death.

Neuronal nitric oxide synthase (nNOS) and p38MAPK are strongly implicated in excitotoxicity, a mechanism common to many neurodegenerative conditions, but the intermediary mechanism is unclear. NOS1AP is encoded by a gene recently associated with sudden cardiac death, diabetes-associated complications, and schizophrenia (Arking et al., 2006; Becker et al., 2008; Brzustowicz, 2008; Lehtinen et al., 2008). Here we find it interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulus induces recruitment of NOS1AP to nNOS in rat cortical neuron culture. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOS1AP interaction and by knockdown with NOS1AP-targeting siRNAs. We designed a cell-permeable peptide that competes for the unique PDZ domain of nNOS that interacts with NOS1AP. This peptide inhibits NMDA-induced recruitment of NOS1AP to nNOS and in vivo in rat, doubles surviving tissue in a severe model of neonatal hypoxia-ischemia, a major cause of neonatal death and pediatric disability. The highly unusual sequence specificity of the nNOS:NOS1AP interaction and involvement in excitotoxic signaling may provide future opportunities for generation of neuroprotectants with high specificity.

The impact of triathlon training and racing on athletes' general health.

Although the sport of triathlon provides an opportunity to research the effect of multi-disciplinary exercise on health across the lifespan, much remains to be done. The literature has failed to consistently or adequately report subject age group, sex, ability level, and/or event-distance specialization. The demands of training and racing are relatively unquantified. Multiple definitions and reporting methods for injury and illness have been implemented. In general, risk factors for maladaptation have not been well-described. The data thus far collected indicate that the sport of triathlon is relatively safe for the well-prepared, well-supplied athlete. Most injuries 'causing cessation or reduction of training or seeking of medical aid' are not serious. However, as the extent to which they recur may be high and is undocumented, injury outcome is unclear. The sudden death rate for competition is 1.5 (0.9-2.5) [mostly swim-related] occurrences for every 100,000 participations. The sudden death rate is unknown for training, although stroke risk may be increased, in the long-term, in genetically susceptible athletes. During heavy training and up to 5 days post-competition, host protection against pathogens may also be compromised. The incidence of illness seems low, but its outcome is unclear. More prospective investigation of the immunological, oxidative stress-related and cardiovascular effects of triathlon training and competition is warranted. Training diaries may prove to be a promising method of monitoring negative adaptation and its potential risk factors. More longitudinal, medical-tent-based studies of the aetiology and treatment demands of race-related injury and illness are needed.

Daytime sleepiness and the COMT val158met polymorphism in patients with Parkinson disease.

STUDY OBJECTIVE: A preliminary study by our group suggested an association between daytime sleepiness and the catechol-O-methyltransferase (COMT) val158met polymorphism (rs4680) in patients with Parkinson disease (PD). We sought to confirm this association in a large group of patients with PD. DESIGN: Genetic association study in patients with PD. SETTING: Movement disorder sections at 2 university hospitals. PARTICIPANTS: PD patients with and without episodes of suddenly falling asleep matched for antiparkinsonian medication, disease duration, sex, and age, who participated in a previous genetic study on dopamine-receptor polymorphisms. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: In this study, 240 patients with PD (154 men; age 65.1 +/- 6.1 years; disease duration 9.4 +/- 6.0 years) were included. Seventy had the met-met (LL), 116 the met-val (LH), and 54 the val-val (HH) genotype. In the combined LL+LH group (featuring reduced COMT activity), the mean Epworth Sleepiness Scale (ESS) score was 9.0 +/- 5.9 versus 11.0 +/- 6.1 in the HH (high COMT activity) group (P = .047). Forty-seven percent of the LL and LH patients had sudden sleep onset compared with 61% of the HH patients (P = .07). Logistic regression, however, showed that both pathologic ESS scores (i.e., > 10) and sudden sleep onset were predicted by subjective disease severity (P < .001 each) but not by the COMT genotype. CONCLUSIONS: Our previous finding that the L-allele may be associated with daytime sleepiness could not be confirmed in the present study. Altogether, our data do not support a clinically relevant effect of the COMT genotype on daytime sleepiness in PD.

Association of ischaemic stroke subtype with long-term cardiovascular events.

BACKGROUND AND PURPOSE: There is no strong evidence that all ischaemic stroke types are associated with high cardiovascular risk. Our aim was to investigate whether all ischaemic stroke types are associated with high cardiovascular risk. METHODS: All consecutive patients with ischaemic stroke registered in the Athens Stroke Registry between 1 January 1993 and 31 December 2010 were categorized according to the TOAST classification and were followed up for up to 10 years. Outcomes assessed were cardiovascular and all-cause mortality, myocardial infarction, stroke recurrence, and a composite cardiovascular outcome consisting of myocardial infarction, angina pectoris, acute heart failure, sudden cardiac death, stroke recurrence and aortic aneurysm rupture. The Kaplan-Meier product limit method was used to estimate the probability of each end-point in each patient group. Cox proportional hazards models were used to determine the independent covariates of each end-point. RESULTS: Two thousand seven hundred and thirty patients were followed up for 48.1 ± 41.9 months. The cumulative probabilities of 10-year cardiovascular mortality in patients with cardioembolic stroke [46.6%, 95% confidence interval (CI) 40.6-52.8], lacunar stroke (22.1%, 95% CI 16.2-28.0) or undetermined stroke (35.2%, 95% CI 27.8-42.6) were either similar to or higher than those of patients with large-artery atherosclerotic stroke (LAA) (28.7%, 95% CI 22.4-35.0). Compared with LAA, all other TOAST types had a higher probability of 10-year stroke recurrence. In Cox proportional hazards analysis, compared with patients with LAA, patients with any other stroke type were associated with similar or higher risk for the outcomes of overall mortality, cardiovascular mortality, stroke recurrence and composite cardiovascular outcome. CONCLUSIONS: Large-artery atherosclerotic stroke and cardioembolic stroke are associated with the highest risk for future cardiovascular events, with the latter carrying at least as high a risk as LAA stroke.

Death Caused by Cardioinhibitory Reflex. What experts believe

The danger of neck compression without restriction of the arterial flow remains unresolved in forensic medicine. There is an ongoing debate concerning life endangerment due to the cardioinhibitory reflex. The aim of this study was to determine what forensic medical experts believe and how they deal with this reflex. An anonymous electronic questionnaire was sent to 1429 forensic medical experts all over the world. We asked them about their opinion on the cardioinhibitory reflex, its role in causing death, and what their diagnostic criteria were.A total of 182 questionnaires were returned. The experts who answered were from 32 different countries. Our survey showed that 80.2% of experts believe that the cardioinhibitory reflex can theoretically cause death. In the practical application opinions diverge though. Apparently, the practical application mainly depends on the habit of the individual expert. We observed no consensus on the diagnostic criteria to be used. Given the potentially frequent use of the concept of the cardioinhibitory reflex in forensic practice and its judicial impact it would be important to reach a consensus.

Simulation of interface dynamics across pore discontinuities

We study the dynamics of a water-oil meniscus moving from a smaller to a larger pore. The process is characterised by an abrupt change in the configuration, yielding a sudden energy release. A theoretic study for static conditions provides analytical solutions of the surface energy content of the system. Although the configuration after the sudden energy release is energetically more convenient, an energy barrier must be overcome before the process can happen spontaneously. The energy barrier depends on the system geometry and on the flow parameters. The analytical results are compared to numerical simulations that solve the full Navier-Stokes equation in the pore space and employ the Volume Of Fluid (VOF) method to track the evolution of the interface. First, the numerical simulations of a quasi-static process are validated by comparison with the analytical solutions for a static meniscus, then numerical simulations with varying injection velocity are used to investigate dynamic effects on the configuration change. During the sudden energy jump the system exhibits an oscillatory behaviour. Extension to more complex geometries might elucidate the mechanisms leading to a dynamic capillary pressure and to bifurcations in final distributions of fluid phases in porous

Evaluation of Variable Advisory Speed Limits in Work Zones, TPF-5(081), 2013

Variable advisory speed limit (VASL) systems could be effective at both urban and rural work zones, at both uncongested and congested sites. At uncongested urban work zones, the average speeds with VASL were lower than without VASL. But the standard deviation of speeds with VASL was higher. The increase in standard deviation may be due to the advisory nature of VASL. The speed limit compliance with VASL was about eight times greater than without VASL. At the congested sites, the VASL were effective in making drivers slow down gradually as they approached the work zone, reducing any sudden changes in speeds. Mobility-wise the use of VASL resulted in a decrease in average queue length, throughput, number of stops, and an increase in travel time. Several surrogate safety measures also demonstrated the benefits of VASL in congested work zones. VASL deployments in rural work zones resulted in reductions in mean speed, speed variance, and 85th percentile speeds downstream of the VASL sign. The study makes the following recommendations based on the case studies investigated: 1. The use of VASL is recommended for uncongested work zones to achieve better speed compliance and lower speeds. Greater enforcement of regulatory speed limits could help to decrease the standard deviation in speeds; 2. The use of VASL to complement the static speed limits in rural work zones is beneficial even if the VASL is only used to display the static speed limits. It leads to safer traffic conditions by encouraging traffic to slow down gradually and by reminding traffic of the reduced speed limit. A well-designed VASL algorithm, like the P5 algorithm developed in this study, can significantly improve the mobility and safety conditions in congested work zones. The use of simulation is recommended for optimizing the VASL algorithms before field deployment.

Assessment of debris-flow susceptibility at medium-scale in the Barcelonnette Basin, France

Debris flows are among the most dangerous processes in mountainous areas due to their rapid rate of movement and long runout zone. Sudden and rather unexpected impacts produce not only damages to buildings and infrastructure but also threaten human lives. Medium- to regional-scale susceptibility analyses allow the identification of the most endangered areas and suggest where further detailed studies have to be carried out. Since data availability for larger regions is mostly the key limiting factor, empirical models with low data requirements are suitable for first overviews. In this study a susceptibility analysis was carried out for the Barcelonnette Basin, situated in the southern French Alps. By means of a methodology based on empirical rules for source identification and the empirical angle of reach concept for the 2-D runout computation, a worst-case scenario was first modelled. In a second step, scenarios for high, medium and low frequency events were developed. A comparison with the footprints of a few mapped events indicates reasonable results but suggests a high dependency on the quality of the digital elevation model. This fact emphasises the need for a careful interpretation of the results while remaining conscious of the inherent assumptions of the model used and quality of the input data.

Cardiologie [Cardiology]

This article reviews: 1) some of the results of drug eluting stents (SYNTAX and FAME); 2) the questionnable benefit of physical training in heart failure patients (HF-ACTION); 3) the benefit on cardiac remodelling of cardiac resynchronisation in heart failure patients (REVERSE study) and 4) the role of rate over rhythm control in patients with atrial fibrillation and heart failure (AF-CHF study); this article also reports the encouraging evolution of new technology allowing percutaneous implantation of stents-valves. Finally, this article address the screening of athletes for cardiac diseases.

Carnitine deficiency in chronic critical illness.

PURPOSE OF REVIEW: New insight in mitochondrial physiology has highlighted the importance of mitochondrial dysfunction in the metabolic and neuroendocrine changes observed in patients presenting with chronic critical illness. This review highlights specifically the importance of carnitine status in this particular patient population and its impact on beta-oxidation and mitochondrial function. RECENT FINDINGS: The main function of carnitine is long chain fatty acid esterification and transport through the mitochondrial membrane. Carnitine depletion should be suspected in critically ill patients with risk factors such as prolonged continuous renal replacement therapy or chronic parenteral nutrition, and evidence of beta-oxidation impairments such as inappropriate hypertriglyceridemia or hyperlactatemia. When fatty acid oxidation is impaired, acyl-CoAs accumulate and deplete the CoA intramitochondrial pool, hence causing a generalized mitochondrial dysfunction and multiorgan failure, with clinical consequences such as muscle weakness, rhabdomyolysis, cardiomyopathy, arrhythmia or sudden death. In such situations, carnitine plasma levels should be measured along with a complete assessment of plasma amino acid, plasma acylcarnitines and urinary organic acid analysis. Supplementation should be initiated if below normal levels (20 μmol/l) of carnitine are observed. In the absence of current guidelines, we recommend an initial supplementation of 0.5-1 g/day. SUMMARY: Metabolic modifications associated with chronic critical illness are just being explored. Carnitine deficiency in critically ill patients is one aspect of these profound and complex changes associated with prolonged stay in ICU. It is readily measurable in the plasma and can easily be substituted if needed, although guidelines are currently missing.