CC chemokine ligands in patients presenting with stable chest pain: association with atherosclerosis and future cardiovascular events

Background

CC chemokine ligands (CCLs) are elevated during acute coronary syndrome (ACS) and correlate with secondary events. Their involvement in plaque inflammation led us to investigate whether CCL3-5-18 are linked to the extent of coronary artery disease (CAD) and prognostic for primary events during follow-up.

Methods

We measured CCL3-5-18 serum concentrations in 712 patients with chest discomfort referred for cardiac CT angiography. Obstructive CAD was defined as ≥50?% stenosis. The extent of CAD was measured by calcium score and segment involvement score (number of coronary segments with any CAD, range 0–16). Patients were followed up for all-cause mortality, ACS and revascularisation, for a mean 26 ± 7 months.

Results

Patients with obstructive CAD had significantly higher CCL5 (p = 0.02), and borderline significantly elevated CCL18 plasma levels as compared with patients with <50?% stenosis (p = 0.06). CCL18 levels were associated with coronary calcification (p = 0.002) and segment involvement score (p = 0.007). Corrected for traditional risk factors, only CCL5 provided independent predictive value for obstructive CAD: odds ratio (OR) 1.27 (1.02–1.59), p = 0.04. CCL5 provided independent predictive value for primary events during follow-up: OR 1.62 (1.03–2.57), p = 0.04.

Conclusions

While CCL18 serum levels correlated with extent of CAD, CCL5 demonstrated an independent association with the presence of obstructive CAD, and occurrence of primary cardiac events.

     

High-Sensitivity Cardiac Troponin Concentrations in Patients with Chest Discomfort: Is It the Heart or the Kidneys As Well?

BackgroundHigh-sensitivity cardiac troponins (hs-cTn) are the preferred biomarkers to detect myocardial injury, making them promising risk-stratifying tools for patients with symptoms of chest pain. However, circulating hs-cTn are also elevated in other conditions like renal dysfunction, complicating appropriate interpretation of low-level hs-cTn concentrations.MethodsA cross-sectional analysis was performed in 1864 patients with symptoms of chest discomfort from the cardiology outpatient department who underwent cardiac computed tomographic angiography (CCTA). Serum samples were analyzed using hs-cTnT and hs-cTnI assays. Renal function was measured by the estimated glomerular filtration rate (eGFR), established from serum creatinine and cystatin C. On follow-up, the incidence of adverse events was assessed.ResultsMedian hs-cTnT and hs-cTnI concentrations were 7.2(5.8–9.2) ng/L and 2.6(1.8–4.1) ng/L, respectively. Multivariable regression analysis revealed that both assay results were more strongly associated with eGFR (hs-cTnT:stβ:-0.290;hs-cTnI:stβ:-0.222) than with cardiac imaging parameters, such as coronary calcium score, CCTA plaque severity score and left ventricular mass (all p<0.01). Furthermore, survival analysis indicated lower relative risks in patients with normal compared to reduced renal function for hs-cTnT [HR(95%CI), 1.02(1.00–1.03) compared to 1.07(1.05–1.09)] and hs-cTnI [1.01(1.00–1.01) compared to 1.02(1.01–1.02)] (all p<0.001).ConclusionIn patients with chest discomfort, we identified an independent influence of renal function on hs-cTn concentrations besides CAD, that affected the association of hs-cTn concentrations with adverse events. Estimating renal function is therefore warranted when interpreting baseline hs-cTn concentrations.     

Trafficking and localization studies of recombinant alpha1, 3- fucosyltransferase VI stably expressed in CHO cells

Peripheral alpha1,3-fucosylation of glycans occurs by the action of either one of five different alpha1,3-fucosyltransferases (Fuc-Ts) cloned to date. Fuc-TVI is one of the alpha1,3-fucosyltransferases which is capable to synthesize selectin ligands. The major alpha1, 3- fucosyltransferase activity in human plasma is encoded by the gene for fucosyltransferase VI, which presumably originates from liver cells. While the sequence, chromosomal localization, and kinetic properties of Fuc-TVI are known, immunocytochemical localization and trafficking studies have been impossible because of the lack of specific antibodies. Here we report on the development and characterization of a peptide-specific polyclonal antiserum monospecific to Fuc-TVI and an antiserum to purified soluble recombinant Fuc-TVI crossreactive with Fuc-TIII and Fuc-TV. Both antisera were applied for immunodetection in stably transfected CHO cells expressing the full-length form of this enzyme (CHO clone 61/11). Fuc-TVI was found to be a resident protein of the Golgi apparatus. In addition, more than 30% of cell-associated and released enzyme activity was found in the medium. Maturation and release of Fuc-TVI was analyzed in metabolically labeled CHO 61/11 cells followed by immunoprecipitation. Fuc-TVI occurred in two forms of 47 kDa and 43 kDa bands, while the secreted form was detected as a 43 kDa. These two different intracellular forms arose by posttranslational modification, as shown by pulse-chase experiments. Fuc-TVI was released to the supernatant by proteolytic cleavage as a partially endo-H resistant glycoform.      

7th SOSORT consensus paper: conservative treatment of idiopathic & Scheuermann's kyphosis

Abstract

Thoracic hyperkyphosis is a frequent problem and can impact greatly on patient's quality of life during adolescence. This condition can be idiopathic or secondary to Scheuermann disease, a disease disturbing vertebral growth. To date, there is no sound scientific data available on the management of this condition. Some studies discuss the effects of bracing, however no guidelines, protocols or indication's of treatment for this condition were found. The aim of this paper was to develop and verify the consensus on managing thoracic hyperkyphosis patients treated with braces and/or physiotherapy.

Methods

The Delphi process was utilised in four steps gradually modified according to the results of a set of recommendations: we involved the SOSORT Board twice, then all SOSORT members twice, with a Pre-Meeting Questionnaire (PMQ), and during a Consensus Session at the SOSORT Lyon Meeting with a Meeting Questionnaire (MQ).

Results

There was an unanimous agreement on the general efficacy of bracing and physiotherapy for this condition. Most experts suggested the use of 4-5 point bracing systems, however there was some controversy with regards to physiotherapeutic aims and modalities.

Conclusion

The SOSORT panel of experts suggest the use of rigid braces and physiotherapy to correct thoracic hyperkyphosis during adolescence. The evaluation of specific braces and physiotherapy techniques has been recommended.     

Paradigm shifts in pathophysiology and management of atrial fibrillation—a tale of the RACE trials in the Netherlands

In the past 20 years the Netherlands-based RACE trials have investigated important concepts in clinical atrial fibrillation (AF). Their scope ranged from rhythm versus rate control to early or delayed cardioversion and also included early comprehensive management of AF in two trials, one focusing on early ‘upstream therapy’ and risk factor management and the other on integrated chronic nurse-led care. Studies were mostly triggered by simple clinical observations including futility of electrical cardioversion in persistent AF; many patients with permanent AF tolerating day-after-day ‘uncontrolled’ resting heart rates of up till 110 beats/min; patients being threatened more by vascular risks than AF itself; and insufficient guideline-based treatments for AF. Also the observation that recent-onset atrial fibrillation generally converts spontaneously, obviating cardioversion, triggered one of the studies. The RACE trials shifted a number of paradigms and by that could change the AF guidelines. The initial ‘shock-and-forget’ attitude made place for increased attention for anticoagulation, and in turn, broader vascular risks were recognised. In a nutshell, the adage eventually became: ‘look beyond the ECG, treat the patient’.

     

Disentangling Woodland Caribou Movements in Response to Clearcuts and Roads across Temporal Scales

Although prey species typically respond to the most limiting factors at coarse spatiotemporal scales while addressing biological requirements at finer scales, such behaviour may become challenging for species inhabiting human altered landscapes. We investigated how woodland caribou, a threatened species inhabiting North-American boreal forests, modified their fine-scale movements when confronted with forest management features (i.e. clearcuts and roads). We used GPS telemetry data collected between 2004 and 2010 on 49 female caribou in a managed area in Québec, Canada. Movements were studied using a use – availability design contrasting observed steps (i.e. line connecting two consecutive locations) with random steps (i.e. proxy of immediate habitat availability). Although caribou mostly avoided disturbances, individuals nonetheless modulated their fine-scale response to disturbances on a daily and annual basis, potentially compromising between risk avoidance in periods of higher vulnerability (i.e. calving, early and late winter) during the day and foraging activities in periods of higher energy requirements (i.e. spring, summer and rut) during dusk/dawn and at night. The local context in which females moved was shown to influence their decision to cross clearcut edges and roads. Indeed, although females typically avoided crossing clearcut edges and roads at low densities, crossing rates were found to rapidly increase in greater disturbance densities. In some instance, however, females were less likely to cross edges and roads as densities increased. Females may then be trapped and forced to use disturbed habitats, known to be associated with higher predation risk. We believe that further increases in anthropogenic disturbances could exacerbate such behavioural responses and ultimately lead to population level consequences.     

Reliable identification at the species level of Brucella isolates with MALDI-TOF-MS

Background

Brucella abortus is the etiological agent of a worldwide zoonosis called brucellosis. This alpha-proteobacterium is dividing asymmetrically, and PdhS, an essential histidine kinase, was reported to be an old pole marker.

Results

We were interested to identify functions that could be recruited to bacterial poles. The Brucella ORFeome, a collection of cloned predicted coding sequences, was placed in fusion with yellow fluorescent protein (YFP) coding sequence and screened for polar localizations in B. abortus. We report that AidB-YFP was systematically localized to the new poles and at constrictions sites in B. abortus, either in culture or inside infected HeLa cells or RAW264.7 macrophages. AidB is an acyl-CoA dehydrogenase (ACAD) homolog, similar to E. coli AidB, an enzyme putatively involved in destroying alkylating agents. Accordingly, a B. abortus aidB mutant is more sensitive than the wild-type strain to the lethality induced by methanesulphonic acid ethyl ester (EMS). The exposure to EMS led to a very low frequency of constriction events, suggesting that cell cycle is blocked during alkylation damage. The localization of AidB-YFP at the new poles and at constriction sites seems to be specific for this ACAD homolog since two other ACAD homologs fused to YFP did not show specific localization. The overexpression of aidB, but not the two other ACAD coding sequences, leads to multiple morphological defects.

Conclusions

Data reported here suggest that AidB is a marker of new poles and constriction sites, that could be considered as sites of preparation of new poles in the sibling cells originating from cell division. The possible role of AidB in the generation or the function of new poles needs further investigation.     

Feasibility of TEE-guided stroke risk assessment in atrial fibrillation—background, aims, design and baseline data of the TIARA pilot study

Background

Antithrombotic management in atrial fibrillation (AF) is currently based on clinical characteristics, despite evidence of potential fine-tuning with transoesophageal echocardiography (TEE). This open, randomised, multicentre study addresses the hypothesis that a comprehensive strategy of TEE-based aspirin treatment in AF patients is feasible and safe.

Methods

Between 2005 and 2009, ten large hospitals in the Netherlands enrolled AF patients with a moderate risk of stroke. Patients without thrombogenic TEE characteristics were randomised to aspirin or vitamin K antagonists (VKA). The primary objective is to show that TEE-based aspirin treatment is safe compared with VKA therapy. The secondary objective tests feasibility of TEE as a tool to detect echocardiographic features of high stroke risk. This report compares randomised to non-randomised patients and describes the feasibility of a TEE-based approach.

Results

In total, 310 patients were included. Sixty-nine patients were not randomised because of non-visualisation (n = 6) or TEE risk factors (n = 63). Compared with non-randomised patients, randomised patients (n = 241) were younger (65 ± 11 vs. 69 ± 9 years, p = 0.004), had less coronary artery disease (9 vs. 20%, p = 0.018), previous TIA (1.7 vs. 7.2%, p = 0.029), AF during TEE (25 vs. 54%, p < 0.001), mitral incompetence (55 vs. 70%, p = 0.038), VKA use (69 vs. 82%, p = 0.032), had a lower mean CHADS₂ score (1.2 ± 0.6 vs. 1.6 ± 1.0, p = 0.004), and left ventricular ejection fraction (59 ± 8 vs. 56 ± 8%, p = 0.016).

Conclusions

This study shows that a TEE-based approach for fine-tuning stroke risk in AF patients with a moderate risk for stroke is feasible. Follow-up data will address the safety of this TEE-based approach.     

Functional characterization and target discovery of glycoside hydrolases from the digestome of the lower termite Coptotermes gestroi

Background

Lignocellulosic materials have been moved towards the forefront of the biofuel industry as a sustainable resource. However, saccharification and the production of bioproducts derived from plant cell wall biomass are complex and lengthy processes. The understanding of termite gut biology and feeding strategies may improve the current state of biomass conversion technology and bioproduct production.

Results

The study herein shows comprehensive functional characterization of crude body extracts from Coptotermes gestroi along with global proteomic analysis of the termite's digestome, targeting the identification of glycoside hydrolases and accessory proteins responsible for plant biomass conversion. The crude protein extract from C. gestroi was enzymatically efficient over a broad pH range on a series of natural polysaccharides, formed by glucose-, xylose-, mannan- and/or arabinose-containing polymers, linked by various types of glycosidic bonds, as well as ramification types. Our proteomic approach successfully identified a large number of relevant polypeptides in the C. gestroi digestome. A total of 55 different proteins were identified and classified into 29 CAZy families. Based on the total number of peptides identified, the majority of components found in the C. gestroi digestome were cellulose-degrading enzymes. Xylanolytic enzymes, mannan- hydrolytic enzymes, pectinases and starch-degrading and debranching enzymes were also identified. Our strategy enabled validation of liquid chromatography with tandem mass spectrometry recognized proteins, by enzymatic functional assays and by following the degradation products of specific 8-amino-1,3,6-pyrenetrisulfonic acid labeled oligosaccharides through capillary zone electrophoresis.

Conclusions

Here we describe the first global study on the enzymatic repertoire involved in plant polysaccharide degradation by the lower termite C. gestroi. The biochemical characterization of whole body termite extracts evidenced their ability to cleave all types of glycosidic bonds present in plant polysaccharides. The comprehensive proteomic analysis, revealed a complete collection of hydrolytic enzymes including cellulases (GH1, GH3, GH5, GH7, GH9 and CBM 6), hemicellulases (GH2, GH10, GH11, GH16, GH43 and CBM 27) and pectinases (GH28 and GH29).