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Aims: Risk stratification models of sudden cardiac death (SCD) are based on the assumption that risk factors of SCD affect risk to a similar extent in both sexes. The aim of the study is to evaluate differences in clinical outcomes between sexes and evaluate whether risk factors associated with appropriate device therapy (ADT) differ between men and women. Methods and results: We performed a cohort study of implantable cardioverter defibrillator (ICD) patients referred for primary or secondary prevention of SCD between 2009 and 2018. Multivariable Cox regression models for prediction of ADT were constructed for men and women separately. Of 2300 included patients, 571 (25%) were women. Median follow-up was 4.6 (inter-quartile range: 4.4–4.9) years. Time to ADT was shorter for men compared with women [hazard ratio (HR) 1.71, P

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [ 11 C]-hydroxyephedrine positron emission tomography ([ 11 C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity. [ 11 C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [ 11 C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [ 11 C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [ 11 C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [ 11 C]HED retention index was lower compared to LV tracer uptake (p

Funding Acknowledgements Type of funding sources: None. Background Psychological distress, such as symptoms of anxiety and depression, are frequently present in patients receiving an implantable cardioverter defibrillator (ICD) and they are associated with adverse outcomes. Multiple pathophysiological mechanisms may explain the link between psychological distress and cardiovascular disease, such as autonomic dysfunction, neuro-endocrine alterations and chronic inflammation. Purpose The present study aims to examine the prevalence of psychological distress at time of ICD implantation and evaluates the complex interplay between psychological distress, autonomic function, neuro-endocrine alterations and inflammatory status in ICD patients. Methods We conducted a prospective study that included ICD patients receiving an ICD for primary and secondary prevention of sudden cardiac death. Prior to implantation, patients underwent extensive psychological evaluation, including validated questionnaires for depression, anxiety and personality traits. Cardiac status was evaluated by left ventricular ejection fraction (LVEF) assessment, New York Heart Association (NYHA) functional class evaluation, 6-minute walk test (6MWT), and 24-hour Holter monitoring for heart rate variability (HRV). Thyroid function, catecholamine levels and inflammatory status were also evaluated. Results Of 178 patients included (age 64 ± 12, 79% male, LVEF 35 ± 13%), 35% had symptoms of depression and 32% had symptoms of anxiety. Symptoms of depression and anxiety increased significantly with higher NYHA functional class (P Conclusion A substantial part of ICD patients has symptoms of depression and anxiety at time of ICD implantation. Depression was correlated with a higher NYHA class, reduced exercise capacity, reduced LV-function and alterations in autonomic function, suggesting a biological link between depression and cardiac status. Whether depression and anxiety leads to an increase in ventricular arrhythmias will be determined during further follow-up. Abstract Figure. NYHA class and psychological distress

Background In survivors of sudden cardiac arrest with obstructive coronary artery disease, it remains challenging to distinguish ischemia as a reversible cause from irreversible scar‐related ventricular arrhythmias. We aimed to evaluate the value of implantable cardioverter‐defibrillator (ICD) implantation in sudden cardiac arrest survivors with presumably reversible ischemia and complete revascularization. Methods and Results This multicenter retrospective cohort study included 276 patients (80% men, age 67±10 years) receiving ICD implantation for secondary prevention. Angiography was performed before ICD implantation. A subgroup of 166 (60%) patients underwent cardiac magnetic resonance imaging with late gadolinium enhancement before implantation. Patients were divided in 2 groups, (1) ICD‐per‐guideline, including 228 patients with incomplete revascularization or left ventricular ejection fraction ≤35%, and (2) ICD‐off‐label, including 48 patients with complete revascularization and left ventricular ejection fraction >35%. The primary outcome was time to appropriate device therapy (ADT). During 4.0 years (interquartile range, 3.5–4.6) of follow‐up, ADT developed in 15% of the ICD‐off‐label group versus 43% of the ICD‐per‐guideline group. Time to ADT was comparable in the ICD‐off‐label and ICD‐per‐guideline groups (hazard ratio (HR), 0.46; P =0.08). No difference in mortality was observed (HR, 0.95; P =0.93). Independent predictors of ADT included age (HR, 1.03; P =0.01), left ventricular end‐diastolic volume HR, (1.05 per 10 mL increase; P P =0.04). Conclusions This study demonstrates that sudden cardiac arrest survivors with coronary artery disease remain at high risk of recurrent ventricular arrhythmia, even after complete revascularization and with preserved left ventricular function. Late gadolinium enhancement–cardiac magnetic resonance imaging derived left ventricular volumes and extent of myocardial scar were independently associated with.

Background Implantable cardioverter defibrillator (ICD) guidelines and risk stratification models of sudden cardiac death (SCD) are applied without differentiation between men and women, based on the assumption that the incidence of ventricular arrhythmias and risk factors of SCD are similar in both sexes. Sex-specific risk factors of SCD may influence studies evaluating the benefit of ICD therapy, for both men and women. Purpose Aim of the study is to assess sex-specific differences in occurrence and predictors of appropriate device therapy (ADT) for ventricular arrhythmias. Methods A multicenter retrospective cohort of 2300 consecutive patients was evaluated, including patients referred for ICD implantation between the years 2009–2018 (age 62±13 years, LVEF 32±12%, 53% ischemic cardiomyopathy [CMP], 28% resynchronization therapy, 65% primary prevention). Exclusion criteria were: (1) patients with hypertrophic CMP, arrhythmogenic right ventricular CMP, systemic infiltrative cardiac disease or channelopathy; (2) lost to follow-up immediately after ICD implantation. Primary endpoint was ADT, defined as anti-tachycardia pacing or shock for ventricular tachyarrhythmia. Secondary endpoints were mortality and inappropriate ICD therapy. Univariable and multivariable Cox regression analyses, stratified by sex, were performed to assess predictors of ADT. Results The cohort primarily consisted of men (75%). After a mean follow-up of 4.8±3.0 years, men experienced more ADT compared to women (25% versus 16%, HR 1.71, p Conclusion This study showed that men were at higher risk of ADT compared to women and that risk factors associated with SCD differ between both sexes. The results strongly suggests that SCD risk stratification models are primarily driven by male patients and sex-specific risk models of SCD are needed to identify those women at high risk of SCD. Figure 1 Funding Acknowledgement Type of funding source: None

Objectives: This study presents a head-to-head comparison of the value of cardiac magnetic resonance (CMR)-derived left-ventricular (LV) function and scar burden and positron emission tomography (PET)-derived perfusion and innervation in predicting ventricular arrhythmias (VAs). Background: Improved risk stratification of VA is important to identify patients who should benefit of prophylactic implantable cardioverter-defibrillator (ICD) implantation. Perfusion abnormalities, sympathetic denervation, and scar burden have all been linked to VA, although comparative studies are lacking. Methods: Seventy-four patients with ischemic cardiomyopathy and left-ventricular ejection fraction (LVEF) ≤35%, referred for primary prevention ICD placement were enrolled prospectively. Late gadolinium-enhanced (LGE) CMR was performed to assess LV function and scar characteristics. [ 15O]H 2O and [ 11C]hydroxyephedrine positron emission tomography (PET) were performed to quantify resting and hyperemic myocardial blood flow (MBF), coronary flow reserve (CFR), and sympathetic innervation. During follow-up of 5.4 ± 1.9 years, the occurrence of sustained VA, appropriate ICD therapy, and mortality were evaluated. Results: In total, 20 (26%) patients experienced VA. CMR and PET parameters showed considerable overlap between patients with VA and patients without VA, caused by substantial heterogeneity within groups. Univariable analyses showed that lower LVEF (hazard ratio [HR]: 0.92; p = 0.03), higher left-ventricular end-diastolic volume index (LVEDVi) (HR 1.02; p < 0.01), and larger scar border zone (HR 1.11; p = 0.03) were related to VA. Scar core size, resting MBF, hyperemic MBF, perfusion defect size, innervation defect size, and the innervation-perfusion mismatch were not found to be associated with VA. Conclusions: In patients with ischemic cardiomyopathy, lower LVEF, higher LVEDVi, and larger scar border zone were related to VA. PET-derived perfusion and sympathetic innervation, as well as CMR-derived scar core size were not associated with VA. These results suggest that improved prediction of VA by advanced imaging remains challenging for the individual patient.

Background To improve uptake of ACP, primary care providers (PCP; general practitioners (GPs), community nurses, certified nursing assistants, practice nurses) were trained in ACP and received support during implementation. Methods ACP was implemented in 10 GP-practices and 2 care homes. Before implementation a list was drawn up of all patients of 75 years or older in the GP practice or care home on 01-01-2017. On this list, PCP made a note of patients with whom they started a ACP conversation until 14 months after start of implementation. Also, questionnaires were sent to the patients before and 14 months after start of implementation. Now we present interim analyses, at the conference the final data will be available. Results A total of 2292 older patients were enrolled with the GP practices or living in the nursing homes. Of those, 596 (26%) received an offer of ACP and/or had an ACP conversation. The conversation was started more often with older patients (mean age 81 versus 83 years); female patients (57% versus 64%), and patients with at least one diagnosis (88% versus 95%). Questionnaires show an increase in advance directives (31.1% versus 41.0%) after implementation, compared to before implementation. Conclusions With a quarter of older patients an ACP conversation was started (ACP was offered and/or an ACP conversation was held). Advance directives are drawn up more often after implementation of ACP. Care providers make a selection in patients with whom they start the conversation.

Contains fulltext : 176957.pdf (Publisher’s version ) (Open Access) Impaired left atrial emptying fraction (LAEF) is an important predictor of mortality in patients with heart failure. As it may reflect increased LV wall stress, it might predict ventricular arrhythmia (VA) specifically. This study evaluated the predictive value of LAEF assessed with cardiovascular magnetic resonance (CMR) imaging with respect to appropriate device therapy (ADT) for VA and compared its role with CMR assessed scar size and other risk factors. In total, 229 patients (68% male, 63 +/- 10 years, 61% ischemic cardiomyopathy) with LV ejection fraction median and scar size < median were at low risk (13% ADT at 5 years), whereas those with LAEF < median and scar size > median experienced 40% ADT at 5 years (log-rank p = 0.01). In conclusion, LAEF independently predicts ADT in patients with primary prevention ICDs. Combined assessment of LAEF and scar size identifies a group with low risk of ADT. Therefore, LAEF assessment could assist in risk stratification for VA to select patients with the highest benefit from ICD implantation.

Recommendations for prophylactic implantable cardioverter defibrillator (ICD) implantation in asymptomatic heart failure patients with a reduced left ventricular ejection fraction (LVEF) differ between guidelines. Evidence on the risk of appropriate device therapy (ADT) and death in New York Heart Association (NYHA) class I patients is scarce. Aim of this study is to evaluate ADT and mortality in NYHA-I primary prevention ICD patients with a LVEF ≤35%. A retrospective cohort was studied, including 572 patients with LVEF ≤35% who received a prophylactic ICD with or without resynchronization therapy (CRT-D). To evaluate the incidence of ADT and mortality, NYHA-I was compared with NYHA-II-III using Cox regression analysis. During a follow-up of 4.1 ± 2.4 years, 33% of the NYHA-I patients received ADT compared with 20% of the NYHA-II-III patients (hazard ratio 1.5, 95% confidence interval 1.04 to 2.31, p = 0.03). No differences in mortality were observed (hazard ratio 0.70, 95% confidence interval 0.49 to 1.07, p = 0.10). Additional analyses showed no difference in time to ADT excluding CRT patients (ICD-NYHA-I patients vs ICD-NYHA-II-III patients, p = 0.17) and comparing ischemic and nonischemic cardiomyopathy NYHA-I patients (p = 0.13). Multivariable Cox regression analyses showed that NYHA class was the strongest independent predictor of ADT. In conclusion, primary prevention NYHA-I ICD patients showed a higher incidence of ADT compared with NYHA-II-III ICD patients. These results strongly suggest that primary prevention NYHA-I patients with a LVEF ≤35% are likely to benefit from ICD therapy and should not be excluded from a potentially life-saving therapy.

When milk powder is examined for the presence of salmonellae using a volume of preenrichment medium three times or more that of the milkpowder, false-negative results may be obtained. Reconstitution for half an hour at room temperature using an amount of medium twice the volume of the milk powder, before further dilution and preenrichment, increased Salmonella recovery.

Objectives The randomized clinical VANISH (Impact of Vascular Reparative Therapy on Vasomotor Function and Myocardial Perfusion: A Randomized [15O]H2O PET/CT Study) trial was conducted to assess quantitative myocardial blood flow (MBF) during resting, hyperemia, and cold pressor testing (CPT) with positron emission tomographic perfusion imaging after the implantation of a bioresorbable everolimus-eluting scaffold compared with a drug-eluting stent. Background Long-term resorption of the bioresorbable everolimus-eluting scaffold reinstates normal vessel geometry, allowing natural regeneration of the newly formed endothelium with revival of vasomotor function. Methods Sixty patients (18 to 65 years of age) with single-vessel disease and type A or B1 lesions were randomized in a 1-to-1 fashion. Approximately 1 month, 1 year, and 3 years after device implantation, patients underwent [15O]H2O cardiac positron emission tomography. The primary endpoint was the interaction of device type and evolution over time of hyperemic MBF, coronary flow reserve, or CPT reserve. At 3-year follow-up, control invasive coronary angiography with optical coherence tomography was performed. Results Fifty-nine (98%), 56 (93%), and 51 (85%) patients successfully completed 1-month, 1-year, and 3-year follow-up positron emission tomography, respectively, and no culprit vessel events were registered during follow-up time. The primary study endpoint (i.e., interaction between device type and time) was nonsignificant for hyperemic MBF, CPT reserve, and coronary flow reserve (p > 0.05 for all). In all patients, hyperemic MBF decreased from 1 to 3 years (p = 0.02), while coronary flow reserve was lower at 3-year follow-up compared with 1-month and 1-year follow-up (p = 0.03 for both). After 3 years, percentage area stenosis measured with optical coherence tomography was higher within the bioresorbable everolimus-eluting scaffold compared with the drug-eluting stent (p = 0.03). Conclusions The hypothesized beneficial effects of scaffold resorption did not translate to improved MBF during maximal hyperemia or endothelium-dependent vasodilation by CPT.

BACKGROUND: Failure to induce oral tolerance may result in food allergy. Hydrolysed cow's milk-based infant formulas are recommended in subjects with a high risk of developing allergic disease. Presentation of T cell epitopes is a prerequisite to generate regulatory T cells that could contribute to oral tolerance. OBJECTIVE: To investigate whether a specific hydrolysed whey-based infant formula contains peptides that function as T cell epitopes to support the development of oral tolerance to whey. METHODS: First, a novel liquid chromatography-mass spectrometry (LC-MS) method was developed to characterize β-lactoglobulin-derived peptides present in a specific infant formula with a focus on region AA#13-48 of β-lactoglobulin, which has previously been described to contain T cell epitopes with tolerogenic potential. Second, the formula was subjected to the ProImmune ProPresent® antigen presentation assay and MHC class II binding algorithm to identify relevant HLA-DRB1-restricted peptides. Third, identified peptides were tested on human cow's milk protein-specific T cell lines to determine T cell recognition. RESULTS: Thirteen peptides of minimal 9AAs long that overlap with AA#13-48 of β-lactoglobulin were identified. Six of them were found across all batches analysed. It was further confirmed that these peptides were processed and presented by human dendritic cells. The identified HLA-DRB1-restricted peptides were correlated to AA#11-30 and AA#23-39 of β-lactoglobulin. Importantly, the proliferation assay showed that the synthetic peptides were recognized by cow's milk protein-specific T cell lines and induced T cell proliferation. CONCLUSION AND CLINICAL RELEVANCE: This study demonstrates that the tested hydrolysed infant formula contains functional HLA-DRB1-restricted T cell epitopes, which can potentially support the development of oral tolerance to whey.

Background: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in infancy with a complex pathology. In adults, the clinical severity of AD has been associated with increases in T helper cell type (Th) 2, Th22, and Th17 serum markers, including high levels of CC chemokine ligand (CCL) 17 and CCL22 chemokines.Objective: To explore the possible association between serum chemokine levels and AD severity in infants with moderate-to-severe AD and elevated immunoglobulin E (IgE).Subjects and methods: Serum samples (n = 41) obtained from a randomized, double-blind, and clinical dietary intervention study were used to study biomarkers in infants with AD. Baseline- and post-intervention samples (4 months) were used, six chemokines and nine ratios thereof were analyzed using Luminex and correlated to AD severity. In the initial study, the infants were randomized to receive extensively hydrolyzed whey-based formula without (control) or with short-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (9:1) and Bifidobacterium breve M-16V (active).Results: 31 Infants up to 11 months of age, with an objective-SCORAD score (oSCORAD) ≥ 20 and elevated total-IgE and/or specific-IgE levels were included. In time, the median oSCORAD decreased in both groups by -8 (control, p Conclusion: While this study is small and exploratory in nature, these data contribute to immune biomarker profiling and understanding of AD in infants.

Mismatch between myocardial innervation and perfusion assessed with positron emission tomography (PET) is a potential risk marker for ventricular arrhythmias in patients with ischemic cardiomyopathy. This mismatch zone originates from residual viable myocardium that has sustained ischemic nerve injury. Heterogenic scar size assessed with late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR) is also a risk marker of ventricular arrhythmias. These two imaging parameters may represent identical morphological tissue features. The current study explored the relation between innervation-perfusion mismatch and heterogenic scar size. Twenty-eight patients (26 males, age 67 ± 8 years) with ischemic cardiomyopathy and a left ventricular ejection fraction below 35%, eligible for ICD implantation were included. All patients underwent both [11C]-hydroxyephedrine and [15O]-water PET studies to assess myocardial sympathetic innervation and perfusion. LGE CMR was conducted to assess total myocardial scar size, scar core size, and heterogenic scar size. Perfusion defect size was 16.6 ± 9.9% and innervation defect size was 33.7 ± 10.8%, which resulted in an innervation-perfusion mismatch of 17.6 ± 8.9%. Total scar size, scar core size, and heterogenic scar size were 21.2 ± 8.6%, 14.7 ± 6.6%, and 6.5 ± 2.9%, respectively. No relation between scar core size and perfusion deficit size was observed (r = 0.18, P = .36). Total scar size was correlated with the innervation defect size (r = 0.52, P = .004) and the heterogenic scar zone displayed a significant correlation with the innervation-perfusion mismatch area (r = 0.67, P

The main eligibility criterion for primary prevention implantable cardioverter defibrillator (ICD) therapy, that is, left ventricular ejection fraction (LVEF), is based on large clinical trials using primarily 2-dimensional echocardiography (2DE). Presently, cardiac magnetic resonance imaging (MRI) is considered the gold standard for LVEF assessment. It has been demonstrated that cardiac MRI assessment results in lower LVEFs compared with 2DE. Consequently, cardiac MRI-LVEF assessment may lead to more patients eligible for ICD implantation with potential clinical consequences. The aim of this study was to evaluate the clinical impact of cardiac MRI-LVEF versus 2DE-LVEF assessment for ICD eligibility. A total of 149 patients with cardiac MRI-LVEF ≤35% referred for primary prevention ICD implantation who underwent both 2DE and cardiac MRI-LVEF assessment were retrospectively included. 2DE-LVEF was computed by Simpson's biplane method. Cardiac MRI-LVEF was computed after outlining the endocardial contours in short-axis cine images. Appropriate device therapy (ADT) and all-cause mortality were evaluated during 2.9 ± 1.7 years of follow-up. The present study found that cardiac MRI-LVEF was significantly lower compared with 2DE-LVEF (23 ± 8% vs 30 ± 8%, respectively, p0.001), resulting in 29 (19%) more patients eligible for ICD implantation according to the current guidelines (LVEF ≤35%). Patients with 2DE-LVEF35% but cardiac MRI-LVEF ≤35% experienced a lower ADT rate compared with patients having 2DE-LVEF ≤35% (2.1% vs 10.4% per year, respectively, p = 0.02). Application of cardiac MRI-LVEF cutoff of 30% resulted in 119 eligible patients experiencing 9.9% per year ADT, comparable with 2DE-LVEF cut-off value of 35%. In conclusion, cardiac MRI-LVEF assessment resulted in more patients eligible for ICD implantation compared with 2DE who showed a relatively low event rate during follow-up. The event rate in patients with cardiac MRI-LVEF ≤30% was comparable with patients having a 2DE-LVEF ≤35%. This study suggests the need for re-evaluation of cardiac MRI-based LVEF cut-off values for ICD eligibility.

Aims Sympathetic denervation typically occurs in the infarcted myocardium and is associated with sudden cardiac death. Impaired innervation was also demonstrated in non-infarcted myocardium in ischaemic and dilated cardiomyopathy (ICMP and DCMP). Factors affecting sympathetic nerve integrity in remote myocardium are unknown. Perfusion abnormalities, even in the absence of epicardial coronary artery disease, may relate to sympathetic dysfunction. This study was aimed to assess the interrelations of myocardial blood flow (MBF), contractile function, and sympathetic innervation in non-infarcted remote myocardium. Methods and results Seventy patients with ICMP or DCMP and LVEF ≤35% were included. [15O]H2O- and [11C]hydroxyephedrine (HED) PET was performed to quantify resting MBF, hyperaemic MBF, and sympathetic innervation. Cardiovascular magnetic resonance (CMR) imaging was performed to assess left ventricular function, mass, wall thickening, and scar size. Wall thickening, [11C]HED retention index (RI), and MBF were assessed in remote segments without scar, selected on CMR. [11C]HED RI was correlated with resting MBF ( r = 0.41, P < 0.001) and hyperaemic MBF ( r = 0.55, P < 0.001) in remote myocardium in both ICMP and DCMP. In addition, LV volumes ( r = −0.40, P = 0.001), LV mass ( r = −0.31, P = 0.008), and wall thickening ( r = 0.45, P < 0.001) correlated with remote [11C]HED RI. Multivariable analysis revealed that hyperaemic MBF ( B = 0.79, P < 0.001), wall thickening ( B = 0.01, P = 0.03), and LVEDV ( B = −0.03, P = 0.02) were independent predictors for remote [11C]HED RI. Conclusion Hyperaemic MBF is independently associated with sympathetic innervation in non-infarcted remote myocardium in patients with ICMP and DCMP. This suggests that microvascular dysfunction might be an important factor related to sympathetic nerve integrity. Whether impaired hyperaemic MBF is the primary cause of this relation remains unclear.

Item does not contain fulltext Aims: Previous studies on invasive assessment of collateral function in patients with a chronic total occlusion (CTO) have displayed only a limited increase in collateral flow and high occurrence of coronary steal during pharmacological stress. This could question the necessity for ischaemia testing prior to revascularization of CTOs in the presence of myocardial viability. The purpose of the present study was to determine the prevalence of perfusion impairments in patients with a CTO as assessed by [15O]H2O positron emission tomography (PET). Methods and results: Seventy-six consecutive patients (60 men, 62 +/- 10 years) with a documented CTO and preserved left ventricular ejection fraction (LVEF) were included. All patients underwent PET to assess (hyperaemic) myocardial blood flow (MBF) and coronary flow reserve (CFR). Collateral connection score was 0 in 7 (9%), 1 in 13 (17%), and 2 in 56 (74%) of the cases, with predominantly a high Rentrop grade (96% >/=2). MBF of the target area during hyperaemia was significantly lower when compared with the remote area (1.37 +/- 0.37 vs. 2.63 +/- 0.71 mL min-1 g-1, P < 0.001). Target to remote ratio during hyperaemia was on average 0.54 +/- 0.13, and 73 (96%) patients demonstrated a significantly impaired target to remote ratio (/=2.50, whereas coronary steal (CFR

Background— Risk stratification for ventricular arrhythmias (VAs) is important to refine selection criteria for primary prevention implantable cardioverter defibrillator therapy. Impaired hyperemic myocardial blood flow (MBF) is associated with increased mortality rate in ischemic and nonischemic cardiomyopathy, which may be attributed to electric instability inducing VAs. The aim of this pilot study was to assess whether hyperemic MBF impairment may be related with VA inducibility in patients with ischemic cardiomyopathy. Methods and Results— Thirty patients with ischemic cardiomyopathy referred for primary prevention implantable cardioverter defibrillator implantation were prospectively included (26 men; 65±8 years old; left ventricular ejection fraction, 29±6%). [ 15 O]H 2 O positron-emission tomography was performed to quantify resting MBF, hyperemic MBF, and coronary flow reserve. Left ventricular dimensions, function, and scar burden were assessed with cardiovascular magnetic resonance imaging. An electrophysiological study was performed to test VA inducibility. Positive electrophysiological study patients (n=12) showed reduced hyperemic MBF (1.25±0.30 versus 1.66±0.38 mL·min −1 ·g −1 ; P P 75% transmurality was higher ( P Conclusions— In this pilot study, impaired hyperemic MBF and coronary flow reserve were associated with VA inducibility in patients with ischemic cardiomyopathy. These results are hypothesis generating for a potential role of quantitative positron-emission tomography perfusion imaging in risk stratification for VAs.

Myocardial perfusion imaging using positron emission tomography (PET) is a valuable tool in the diagnosis of coronary artery disease. And although PET using [15O]H2O has a high diagnostic accuracy for predicting coronary artery disease in routine clinical practices [(1)][1], left ventricular (LV)

A 61-year-old male patient was referred to our electrophysiology lab for ventricular tachycardia (VT) ablation. The patient had a history of ischaemic cardiomyopathy with impaired left ventricular function and received a dual chamber implantable cardioverter-defibrillator (ICD) after he survived a cardiac arrest. During the past months, the patient suffered from recurrent episodes of monomorphic VT with appropriate ICD therapies. Electrocardiogram suggested an apical origin of the VT. Prior to VT ablation, device interrogation showed a stored supraventricular tracing (Fig. 1).

Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by generating cytotoxic and oxidative stress. Recently, we found that this surface injury is compensated by hyperproliferation and hyperplasia of crypt cells, which was induced by a changed surface to crypt signaling. It is unknown whether this changed signaling is caused by cytotoxic stress and/or oxidative stress, as these processes were never studied separately. The aim of this study was to determine the possible differential effects of dietary heme on these luminal stressors and their impact on the colonic mucosa after 2, 4, 7 and 14 days of heme feeding. Mice received a purified, humanized, control diet or the diet supplemented with 0.2 µmol heme/g. Oxidative and cytotoxic stress were measured in fecal water. Proliferation was determined by Ki67-immunohistochemistry and mucosal responses by whole-genome transcriptomics. After heme ingestion, there was an acute increase in reactive oxygen species (ROS) leading to increased levels of lipid peroxidation products. Mucosal gene expression showed an acute antioxidant response, but no change in cell turnover. After day 4, cytotoxicity of the colonic contents was increased and this coincided with differential signaling and hyperproliferation, indicating that cytotoxicity was the causal factor. Simultaneously, several oncogenes were activated, whereas the tumor suppressor p53 was inhibited. In conclusion, luminal cytotoxicity, but not ROS, caused differential surface to crypt signaling resulting in mucosal hyperproliferation and the differential expression of oncogenes and tumor suppressor genes.

Objective Non-invasive imaging of myocardial perfusion, sympathetic denervation and scar size contribute to enhanced risk prediction of ventricular arrhythmias (VA). Some of these imaging parameters, however, may be intertwined as they are based on similar pathophysiology. The aim of this study was to assess the predictive role of myocardial perfusion, sympathetic denervation and scar size on the inducibility of VA in patients with ischaemic cardiomyopathy in a head-to-head fashion. Methods 52 patients with ischaemic heart disease and left ventricular ejection fraction (LVEF) ≤35%, referred for primary prevention implantable cardioverter-defibrillator (ICD) implantation, were included. Late gadolinium-enhanced cardiovascular MRI was performed to assess LV volumes, function and scar size. Using [ 15 O]H 2 O and [ 11 C]hydroxyephedrine positron emission tomography, both resting and hyperaemic myocardial blood flow (MBF), and sympathetic innervation were assessed. After ICD implantation, an electrophysiological study (EPS) was performed and was considered positive in case of sustained VA. Results Patients with a positive EPS (n=25) showed more severely impaired global hyperaemic MBF (p=0.003), larger sympathetic denervation size (p=0.048) and tended to have larger scar size (p=0.07) and perfusion defect size (p=0.06) compared with EPS-negative patients (n=27). No differences were observed in LV volumes, LVEF and innervation-perfusion mismatch size. Multivariable analysis revealed that impaired hyperaemic MBF was the single best independent predictor for VA inducibility (OR 0.78, 95% CI 0.65 to 0.94, p=0.007). A combination of risk markers did not yield incremental predictive value over hyperaemic MBF alone. Conclusions Of all previously validated approaches to evaluate the arrhythmic substrate, global impaired hyperaemic MBF was the only independent predictor of VA inducibility. Moreover, a combined approach of different imaging variables did not have incremental value.

Background Prevention guidelines for infants at high risk of allergic disease recommend hydrolysed formula if formula is introduced before 6 months, but evidence is mixed. Adding specific oligosaccharides may improve outcomes. Objective To evaluate whether partially hydrolysed whey formula containing oligosaccharides (0.8 g/100 ml) (pHF‐OS) can prevent eczema in high‐risk infants [ISRCTN65195597]. Methods We conducted a parallel‐group, multicentre, randomized double‐blind controlled trial of pHF‐OS vs standard cow's milk formula. Infants with a family history of allergic disease were randomized (stratified by centre/maternal allergy) to active (n = 432) or control (n = 431) formula until 6 months of age if formula was introduced before 18 weeks. Primary outcome was cumulative incidence of eczema by 12 months in infants randomized at 0–4 weeks (375 pHF‐OS, 383 control). Secondary outcomes were cumulative incidence of eczema by 12 or 18 months in all infants randomized, immune markers at 6 months and adverse events. Results Eczema occurred by 12 months in 84/293 (28.7%) infants allocated to pHF‐OS at 0‐4 weeks of age, vs 93/324 (28.7%) control (OR 0.98 95% CI 0.68, 1.40; P = 0.90), and 107/347 (30.8%) pHF‐OS vs 112/370 (30.3%) control in all infants randomized (OR 0.99 95% CI 0.71, 1.37; P = 0.94). pHF‐OS did not change most immune markers including total/specific IgE; however, pHF‐OS reduced cow's milk‐specific IgG1 (P < 0.0001) and increased regulatory T‐cell and plasmacytoid dendritic cell percentages. There was no group difference in adverse events. Conclusion pHF‐OS does not prevent eczema in the first year in high‐risk infants. The immunological changes found require confirmation in a separate cohort.

The so-called hygiene hypothesis is, at least in part, accountable for the increase in allergic diseases in the developed countries. Although there is support for one of its primary predictions that host-microbe interactions in early life have longterm effects on the development of disease across populations, the theory has already proven to be imperfect as many more recent increases in certain diseases cannot be explained by the hygiene hypothesis. Nevertheless, many research groups are interested in the host-microbe interactions and are exploring the use of "live micro-organisms which, when administered in adequate amounts, confer a health benefit to the host" (probiotics) and "selectively fermented ingredients that result in specific changes, in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health" (prebiotics) to reduce the allergic disease onset or clinical outcomes. As the definitions of pre- and probiotics by itself were already adapted after their original dictation, it is not surprising that producing generalistic conclusions on the effectiveness of pre-, pro and synbiotic intervention in allergic diseases is very challenging as large differences exist in used species, methodologies, prebiotic(s) (mixtures) and probiotic strains. In this review we elucidate on the hurdles in describing prebiotics, probiotics and the combination being synbiotics in allergic manifestations.

Pathological Q waves may appear on the 12-lead electrocardiogram (ECG) during acute ST-segment elevation myocardial infarction (STEMI) and signify loss of electrical excitation. Anterior wall STEMI often results in loss of R waves in the precordial leads and subsequent appearance of pathological Q waves. Not infrequently, very early loss of R waves may be visible in patients presenting with anterior STEMI and occasionally, these R waves reappear in the first months following the index event. Despite reports in the literature [1–9], the prognostic significance of R-wave reappearance (RWR) in the setting of primary percutaneous coronary intervention (pPCI) remains uncertain. In this report we present two patients with anterior STEMI who underwent uncomplicated pPCI. The follow-up ECGs were indicative of the amount of myocardial recovery after the acute event as shown by cardiovascular magnetic resonance (CMR) imaging.

Traditionally, mast cells were regarded as key cells orchestrating type I hypersensitivity responses. However, it is now recognized that mast cells are widely involved in nonallergic (non-IgE) chronic diseases. Also, in inflammatory bowel disease (IBD), a disease not associated with increased IgE concentrations, clear signs of activation of mast cells have been found. In this study, we investigated if Ig-free L chain-induced hypersensitivity-like responses through activation of mast cells could contribute to the pathophysiology of IBD. As a mast cell-dependent model for IBD, mice were skin-sensitized with dinitrofluorobenzene followed by intrarectal application of the hapten. In this murine IBD model, F991 prevented mast cell activation and also abrogated the development of diarrhea, cellular infiltration, and colonic lymphoid follicle hyperplasia. Furthermore, passive immunization with Ag-specific Ig-free L chains (IgLCs) and subsequent rectal hapten challenge elicited local mast cell activation and increased vascular permeability in the colon of mice. Clinical support is provided by the observation that serum concentrations of IgLCs of patients suffering from Crohn’s disease are greatly increased. Moreover, increased presence of IgLCs was evident in tissue specimens from colon and ileum tissue of patients with IBD. Our data suggest that IgLCs may play a role in the pathogenesis of IBD, which provides novel therapeutic means to prevent or ameliorate the adverse gastrointestinal manifestations of IBD.

Background: No previous studies have compared the effectiveness of different modalities of psychotherapeutic treatment, as defined by different settings and durations, for patients with cluster C personality disorders. The aim of this multicentre study was to compare the effectiveness of 5 treatment modalities for patients with cluster C personality disorders in terms of psychiatric symptoms, psychosocial functioning, and quality of life. The following treatment modalities were compared: long-term outpatient (more than 6 months), short-term day hospital (up to 6 months), long-term day hospital, short-term inpatient, and long-term inpatient psychotherapy. Methods: The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 371 patients with a DSM-IV-TR axis-II cluster C diagnosis. Patients were assigned to 5 different modalities of psychotherapeutic treatment, and effectiveness was assessed at 12 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45), and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. Results: Patients in all treatment groups had improved on all outcomes 12 months after baseline. Patients receiving short-term inpatient treatment showed more improvement than patients receiving other treatment modalities. Conclusions: Psychotherapeutic treatment, especially in the short-term inpatient modality, is an effective treatment for patients with cluster C personality disorders.

Immunoglobulin-free light chains (IgLC) secreted by B lymphocytes, have been shown to mediate hypersensitivity by inducing antigen-specific mast cell activation. Although both mast cells and sensory neurons contribute to the hypersensitivity response, the role of IgLC in relation to sensory neurons is unknown. We therefore aimed to investigate the effects of IgLC on cultures of murine dorsal root ganglion (DRG) neurons. Immunohistochemistry demonstrated that IgLC and IgE could specifically bind to DRG neurons, on which the presence of FceRI, the specific receptor for IgE, was demonstrated by western blotting. Further, optical recordings with Fluo-4 showed that application of the corresponding antigen to IgLC- or IgE-sensitized DRG neurons induces a sustained increase in intracellular Ca2+ in about half of these neurons. These results show that IgLC and IgE can mediate antigen-specific responses in murine neurons. Our findings present a novel way of antigen-specific neuronal activation.

The gastro-intestinal tract is well known for its largest neural network outside the central nervous system and for the most extensive immune system in the body. Research in neurogastroenterology implicates the involvement of both enteric nervous system and immune system in symptoms of inflammatory bowel disease and irritable bowel syndrome. Since both disorders are associated with increased immune cell numbers, nerve growth and activation of both immune cells and nerves, we focus in this review on the involvement of immune cell-nerve interactions in inflammatory bowel disease and irritable bowel syndrome. Firstly, the possible effects of enteric nerves, especially of the nonadrenergic and noncholinergic nerves, on the intestinal immune system and their possible role in the pathogenesis of chronic intestinal inflammatory diseases are described. Secondly, the possible effects of immunological factors, from the innate (chemokines and Toll-like receptors) as well as the adaptive (cytokines and immunoglobulins) immune system, on gastro-intestinal nerves and its potential role in the development of inflammatory bowel disease and irritable bowel syndrome are reviewed. investigations of receptor-mediated and intracellular signal pathways in neuro-immune interactions might help to develop more effective therapeutic approaches for chronic inflammatory intestinal diseases.

Treatment selection in clinical practice is a poorly understood, often largely implicit decision process, perhaps especially for patients with personality disorders. This study, therefore, investigated how intake clinicians use information about patient characteristics to select psychotherapeutic treatment for patients with personality disorder. A structured interview with a forced-choice format was administered to 27 experienced intake clinicians working in five specialist mental health care institutes in the Netherlands. Substantial consensus was evident among intake clinicians. The results revealed that none of the presented patient characteristics were deemed relevant for the selection of the suitable treatment setting. The appropriate duration and intensity are selected using severity or personal strength variables. The theoretical orientation is selected using personal strength variables.

Mast cells are well known as versatile cells capable of releasing and producing a variety of inflammatory mediators upon activation and are often found in close proximity of neurons. In addition, inflammation leads to local activation of neurons resulting in the release neuropeptides, which also play an important immune modulatory role by stimulation of immune cells. In intestinal disorders like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), the number of mast cells is known to be much higher than in the normal intestine. Moreover, both these disorders are also reported to be associated with alterations in neuropeptide content and in neural innervation. Mutual association between mast cells and enteric nerves has been demonstrated to be increased in pathophysiological conditions and contribute to spreading and amplification of the response in IBD and IBS. In this review the focus lies on studies appointed to the direct interaction between mast cells and nerves in IBD, IBS, and animal models for these disorders so far.

Life-threatening ventricular arrhythmias (VA) are a major cause of death in patients with cardiomyopathy. To date, impaired left ventricular ejection fraction remains the primary criterion for implantable cardioverter-defibrillator therapy to prevent sudden cardiac death. In recent years, however, advanced imaging techniques such as nuclear imaging, cardiac magnetic resonance imaging, and computed tomography have allowed for a more detailed evaluation of the underlying substrate of VA. These imaging modalities have emerged as a promising approach to assess the risk of sudden cardiac death. In addition, non-invasive identification of the critical sites of arrhythmias may guide ablation therapy. Typical anatomical substrates that can be evaluated by multiple advanced imaging techniques include perfusion abnormalities, scar and its border zone, and sympathetic denervation. Understanding the principles and techniques of different imaging modalities is essential to gain more insight in their role in identifying the arrhythmic substrate. The current review describes the principles of currently available imaging techniques to identify the substrate of VA.

Background— Quantitative myocardial perfusion imaging is increasingly used for the diagnosis of coronary artery disease. Quantitative perfusion imaging allows to noninvasively calculate fractional flow reserve (FFR). This so-called relative flow reserve (RFR) is defined as the ratio of hyperemic myocardial blood flow (MBF) in a stenotic area to hyperemic MBF in a normal perfused area. The aim of this study was to assess the value of RFR in the detection of significant coronary artery disease. Methods and Results— From a clinical population of patients with suspected coronary artery disease who underwent oxygen-15–labeled water cardiac positron emission tomography and invasive coronary angiography, 92 patients with single- or 2-vessel disease were included. Intermediate lesions (diameter stenosis, 30%–90%; n=75) were interrogated by FFR. Thirty-eight (41%) vessels were deemed hemodynamically significant (>90% stenosis or FFR ≤0.80). Hyperemic MBF, coronary flow reserve, and RFR were lower for vessels with a hemodynamically significant lesion (2.01±0.78 versus 2.90±1.16 mL·min −1 ·g −1 ; P P P r =0.54; P P =0.32 and 0.72; P =0.08, respectively). Conclusions— Noninvasive estimation of FFR by quantitative perfusion positron emission tomography by calculating RFR is feasible, yet only a trend toward a slight improvement of diagnostic accuracy compared with hyperemic MBF assessment was determined.

Inflammatory bowel disease (IBD) describes chronic inflammatory conditions of the gastrointestinal tract, and TNF-alpha plays a pivotal role in mediating the response. The proinflammatory cytokine TNF-alpha is rapidly released by mast cells after degranulation. In the present study, we hypothesized TNF-alpha to be an important player in our recently described mast cell-dependent murine model for IBD. The effect of neutralizing anti-TNF-alpha MAb was studied on colonic hypersensitivity in mice induced by a skin application of dinitrofluorobenzene (DNFB) followed by an intrarectal challenge with dinitrobenzene sulfonic acid. Features of the colonic hypersensitivity response included diarrhea, mast cell infiltration and activation, infiltration of inflammatory cells in the colon, colonic patch hypertrophy, and increased mast cell-derived TNF-alpha levels in the colon. Anti-TNF-alpha MAb could effectively abrogate diarrhea in DNFB-sensitized mice 72 h after the challenge. The numbers of colonic patches and total tissue damage scores were reduced by anti-TNF-alpha MAb treatment in DNFB-sensitized mice 72 h after the challenge. Mast cell infiltration and activation remained unaffected by neutralizing anti-TNF-alpha MAb. Treatment with the corticosteroid dexamethasone, a frequently used therapeutic treatment in IBD, resulted in a reduction of diarrhea, cellular infiltration, and total tissue damage scores to the same extent as anti-TNF-alpha MAb. Additionally, dexamethasone treatment could also reduce total TNF-alpha levels in the colon, mast cell numbers, and mast cell activation in both vehicle- and DNFB-sensitized mice 72 h after the challenge. These findings suggest that TNF-alpha can play an instrumental role in causing inflammatory responses in the present murine model for IBD downstream from mast cell activation.

The immunological mechanisms underlying the role of mast cells in the pathogenesis of inflammatory bowel disease (IBD) are poorly defined. In this study, non-IgE mediated colonic hypersensitivity responses in BALB/c mice induced by skin sensitization with dinitrofluorobenzene (DNFB) followed by an intrarectal challenge with dinitrobenzene sulfonic acid featured as a model to study the role of mast cells in the development of IBD. Vehicle- or DNFB-sensitized mice were monitored for clinical symptoms and inflammation 72 h after dinitrobenzene sulfonic acid challenge. DNFB-sensitized mice developed diarrheic stool, increased colonic vascular permeability, hypertrophy of colonic lymphoid follicles (colonic patches), and showed cellular infiltration at the microscopic level. Increased numbers of mast cells were found in the colon of DNFB-sensitized mice located in and around colonic patches associated with elevated levels of mouse mast cell protease-1 in plasma indicating mast cell activation. Colonic patches of DNFB mice, stimulated in vitro with stem cell factor indicated that an increase in TNF-α levels in the colon is mainly mast cell originated. Finally, neutrophil infiltration was observed in the colon of DNFB-sensitized mice. Induction of this model in mast cell-deficient WBB6F1 W/Wv mice shows a profound reduction of characteristics of the colonic hypersensitivity reaction. Reconstitution with bone marrow-derived mast cells in WBB6F1 W/Wv mice fully restored the inflammatory response. This study demonstrates the importance of mast cells in the development of clinical symptoms and inflammation in the presented murine model for IBD.

Background The aims of this study were to determine the optimal tracer kinetic model for [11C]-meta-hydroxyephedrine ([11C]HED) and to evaluate the performance of several simplified methods. Methods Thirty patients underwent dynamic 60-min [11C]HED scans with online arterial blood sampling. Single-tissue and both reversible and irreversible two-tissue models were fitted to the data using the metabolite-corrected arterial input function. For each model, reliable fits were defined as those yielding outcome parameters with a coefficient of variation (CoV)

The introduction of the implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death has led to an important reduction in mortality in patients with impaired left ventricular ejection fraction (LVEF) [1, 2]. Consequently, current clinical guidelines recommend ICD implantation for primary prevention in patients with an LVEF below 30–40 % [3]. Although the landmark trials upon which these guidelines are based have utilised various imaging modalities to assess LVEF, two-dimensional (2D) echocardiography has been most frequently used to enrol patients. Furthermore, in clinical practice 2D echocardiography is still most commonly performed for this purpose, as it is inexpensive and readily available. In recent years, however, cardiovascular magnetic resonance imaging (CMR) has emerged as the preferred modality to quantify left ventricular volumes and LVEF due to its high reproducibility and accuracy. As such, CMR is often referred to as the gold standard for LVEF assessment [4]. The question arises, whether these imaging modalities are interchangeable for evaluating the eligibility of ICD therapy. This issue becomes particularly relevant in patients with borderline LVEF values (30–40 %) for primary prevention of sudden cardiac death when LVEF is virtually the only parameter to guide such a decision. The study performed by De Haan et al. published in the current issue of the Netherlands Heart Journal included 152 patients who were referred for primary prevention ICD implantation [5]. All patients underwent LVEF assessment by 2D echocardiography as well as CMR within three months prior to device implantation. De Haan et al. report significantly lower values of left ventricular volumes by 2D echocardiography, which on average yielded a higher LVEF of 6.6 %. Although this percentage might sound trivial, from a clinical point of view such an apparent small difference can have great consequences (see Fig. 1). In fact, when taking the most utilised LVEF cut-off value of 35 % by 2D echocardiography to determine device eligibility, 28 % of patients were reclassified when CMR was used as a reference. Apparently, the choice of imaging has a substantial impact on the decision process of selecting appropriate patients for ICD implantation. Obviously, this raises concern and leads to the question which modality to choose. When stakes are that high for the care of our patients, knowledge on the background and characteristics of such imaging modalities becomes imperative. Fig. 1 A 67-year-old patient with ischaemic cardiomyopathy who was screened for ICD implantation for primary prevention of sudden cardiac death. No arrhythmias were documented and the patient did not show signs of heart failure. Both 2D echocardiography and ... The lack of uniformity between imaging modalities to assess LVEF has been well documented. Although comparative studies have shown some discrepancies, most of the data suggest that LVEF tends to be highest when utilising 2D echocardiography and subsequently gradually declines with CMR and nuclear ventriculography, respectively [6]. The quality of echocardiography heavily relies on an adequate acoustic window and bi-plane Simpson’s delineation of the endocardial contours may not be obtained in as many as 30 % of patients. Moreover, 2D echocardiography is based on geometric assumptions of the left ventricle, which poses a source of error in patients with heart failure and LV remodelling. Even with sufficient image quality, the reproducibility of 2D echocardiography has proven to be inferior to CMR [7]. Consequently, many centres nowadays consider CMR to be the imaging modality of choice to screen patients for ICD eligibility. In line with the current results of De Haan et al., Joshi and colleagues have also recently highlighted that CMR guided ICD therapy results in an approximately 25 % augmented implantation rate as compared with echocardiography [8]. Although long-term follow-up and comparison of the event rate of echo vs. CMR driven ICD therapy is lacking, one could logically hypothesise that appropriate ICD therapy for ventricular arrhythmic events will decrease for CMR based implantation when identical LVEF cut-off values are applied. As a consequence, health care costs will steadily rise whereas the relative benefit for our patients diminishes. As correctly pointed out by De Haan et al., the LVEF threshold to guide ICD therapy when utilising CMR should be redefined and will likely need to be adjusted to lower levels. So what should our practice be in the meantime? As current clinical guidelines for ICD implantation are predominantly based on studies using 2D echocardiography, it could be argued that this type of imaging should be preferred to practice evidence-based medicine. Indeed, the ACC/AHA/ESC 2006 guidelines for ICD implantation actually recommend echocardiography for the assessment of left ventricular function [3]. It is of interest to note that the more recent ACC/AHA/HRS 2008 guidelines have nuanced this recommendation and no longer specify an imaging modality to assess LVEF, as long as it is ‘… the most clinically accurate and appropriate in their institution’ [9]. The current data from De Haan et al. remind us that different imaging modalities should certainly not be considered interchangeable and we should be aware what lies beneath the obtained results of a certain requested test to guide the clinical course of our patients. Even though it is clear that CMR holds great potential to act as gatekeeper for ICD therapy, caution on its interpretation is warranted. Future studies should focus on the clinical consequences of CMR based evaluation of ICD eligibility for primary prevention of sudden cardiac death.

Atopic dermatitis (AD) is a complex disorder characterized by flares of red and itchy skin. Infants with AD often also suffer from food allergy. Both ingestion of and skin contact with the antigen can exacerbate the AD. The affected skin is characterized by oedema formation and shows typical Th2 responses by increased levels of IL-4 and IL-13, but not IFN-γ. Furthermore, there is an influx of eosinophils and CD4+ cells. The CD4+ cells are previously described to originate from the gut mucosa where they developed upon oral sensitization to the food allergen. From both specific oligosaccharides and TLR ligands, it is clinically demonstrated that it can affect the development of AD, by skewing the immune response away from an allergic phenotype. In this study, a mouse model to study the effect of dietary compounds on the development and treatment of food allergy-induced AD will be set-up. For this model, BALB/c mice are orally sensitized with ovalbumin (OVA; generally used to induce hen’s egg allergy) plus cholera toxin adjuvant once a week, for 5 consecutive weeks. One week after the last sensitization, the mouse skin will be challenged with OVA on tape-stripped back skin. This is repeated 3 days later, and again 4 days later, the mice are sacrificed. Outcome parameters as skin thickness, inflammatory cell influx and skin mucosal cytokine levels will be studied. Following development of the AD model the effect of dietary intenvention with a combination of specific OS and TLR ligands will be evaluated on the different outcome parameters.

The WHO refers to human milk as the nutritional gold standard for term infants. Human milk contains many immunomodulatory compounds, including oligosaccharides. Human-milk oligosaccharides can serve as prebiotics because the nondigestible oligosaccharides present in human milk show a clear bifidogenic effect on the gut microbiota. Dietary oligosaccharide structures that have prebiotic effects similar to human-milk oligosaccharides include galacto-oligosaccharides, fructo-oligosaccharides, and pectin-derived acidic oligosaccharides. Both animal studies and human clinical trials showed that dietary intervention with these dietary oligosaccharides in early life could lead to the prevention of atopic dermatitis, food allergy, and allergic asthma. The immune-modulating effects of these oligosaccharides are likely assisted via alteration of the intestinal microbiota or in a microbiota-independent manner by direct interaction on immune cells or both. In this review, an overview of the prebiotic role of dietary oligosaccharides on the microbiota and the microbiota-independent immune modulation by these prebiotics is provided. In addition, recent publications that report on the pathways by which the oligosaccharides might exert their direct immunomodulatory effect are summarized.

Plasma B cells secrete immunoglobulinfree light chains (IgLC) which by binding to mast cells can mediate hypersensitivity responses and are involved in several immunological disorders. To investigate the effects of antigen-specific IgLC activation, intracellular recordings were made from cultured murine dorsal root ganglion (DRG) neurons, which can specifically bind IgLC. The neurons were sensitized with IgLC for 90min and subsequently activated by application of the corresponding antigen (DNP-HSA). Antigen application induced a decrease in the rate of rise of the action potentials of non-nociceptive neurons (MANOVA, p=2.10(-6)), without affecting the resting membrane potential or firing threshold. The action potentials of the nociceptive neurons (p=0.57) and the electrical excitability of both types of neurons (p>0.35) were not affected. We conclude that IgLC can mediate antigen-specific responses by reducing the rate of rise of action potentials in non-nociceptive murine DRG neurons. We suggest that antigen-specific activation of IgLC-sensitized non-nociceptive DRG neurons may contribute to immunological hypersensitivity responses and neuroinflammation.

One of the main areas of interest in interventional cardiology is the understanding, and ultimate prevention of restenosis after an initially successful percutaneous transluminal coronary angioplasty. Restenosis is the recurrence of luminal narrowing following angioplasty, and still frustrates the late results in the treatment of angina pectoris. Experimental, pathological and clinical studies suggest that restenosis may occur via activation of the coagulation cascade, platelet activation and thrombus formation. Thrombin itself is identified as the most potent platelet activator, and has a pivotal role in the coagulation system. Furthermore, thrombin directly mediates smooth muscle cell proliferation by stimulating thrombin receptors at the smooth muscle cell surface. Thrombus indirectly induces excessive intimal smooth muscle cell proliferation by means of released mitogens (growth factors), which may contribute to late restenosis. Therefore direct and irreversible thrombin blockade by hirudin is deemed to be effective in the prevention of restenosis following angioplasty. The HELVETICA trial is a multicentre, randomized, double-blind heparin-controlled study, designed to compare the effects of two dose regimens of recombinant-hirudin (CGP 39,393/TMRevasc) with those of heparin on event-free survival, safety, tolerability and luminal renarrowing using quantitative coronary angiography no later than 26 weeks after the coronary angioplasty procedure.

Chronic total occlusions (CTO) with well functioning collaterals are frequently assumed to provide sufficient blood flow to prevent myocardial ischemia. Previous studies on invasive assessment of collateral function during pharmalogical stress, however, have displayed only a limited increase in

Colon cancer is a major cause of cancer deaths in Western countries and is associated with diets high in red meat. Heme, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents which injures surface cells leading to compensatory hyperproliferation of crypt cells. This hyperproliferation results in epithelial hyperplasia which increases the risk of colon cancer. In humans, a high red-meat diet increases Bacteroides spp in feces. Therefore, we simultaneously investigated the effects of dietary heme on colonic microbiota and on the host mucosa of mice. Whole genome microarrays showed that heme injured the colonic surface epithelium and induced hyperproliferation by changing the surface to crypt signaling. Using 16S rRNA phylogenetic microarrays, we investigated whether bacteria play a role in this changed signaling. Heme increased Bacteroidetes and decreased Firmicutes in colonic contents. This shift was most likely caused by a selective susceptibility of Gram-positive bacteria to heme cytotoxic fecal water, which is not observed for Gram-negative bacteria, allowing expansion of the Gram-negative community. The increased amount of Gram-negative bacteria most probably increased LPS exposure to colonocytes, however, there is no appreciable immune response detected in the heme-fed mice. There was no functional change in the sensing of the bacteria by the mucosa, as changes in inflammation pathways and Toll- like receptor signaling were not detected. This unaltered host-microbe cross-talk indicates that the changes in microbiota did not play a causal role in the observed hyperproliferation and hyperplasia.

In 20 patients with pure menstrual migraine either Estraderm TTS 50 patches (E) or placebo (P) patches were applied during three successive menstrual cycles, randomly allocated to the treatment sequences E-P-E or P-E-P. Clinical neurophysiological tests, contingent negative variation (CNV) and exteroceptive temporalis muscle suppression test (ETST) were performed before treatment. The predictive value of these tests regarding the efficacy of Estraderm TTS was studied. Neither the number, duration and severity of the migraine attacks, nor the consumption of analgesics and ergotamine differed significantly during Estraderm TTS and placebo treatment. The ETST was consistent with migraine in 35% (95% confidence interval 15.4 to 59.2) of the patients. The CNV in 55% (31.5 to 76.9), and both tests in 25% (8.7 to 49.1%). Regarding the prediction of the Estraderm TTS effect on the migraine attacks, the specificity of the ETST, CNV and the combination of ETST with CNV, calculated for the first two cycles, was respectively 81.8% (48.2 to 97.7), 45.5% (16.8 to 76.6) and 80% (28.4 to 99.5). For the last two cycles these values were respectively 75% (42.8 to 94.5), 50.0% (21.1 to 87.9) and 71.4% (29.0 to 96.3). The sensitivity of the tests was respectively 62.5% (24.5 to 91.5), 62.5% (24.5 to 91.5) and 66.7% (22.3 to 95.7) in the first 2 cycles. In the last 2 cycles 50.0% (15.1 to 84.3), 62.5% (24.5 to 91.5) and 60% (14.7 to 94.7). This study did not demonstrate an effectiveness of Estraderm TTS in perimenstrual migraine, except for the subgroup of perimenstrual migraine patients in whom the ETST test results were consistent with migraine.

SummaryBackground. Recombinant hirudin (RH) is a new anticoagulant for prophylaxis and treatment of venous and arterial thrombosis. To which extent the activated partial thromboplastin time (APTT) is suitable for monitoring of RH has not been properly evaluated. Recently, a capillary whole blood device was developed for bed-side monitoring of the APTT and it was demonstrated that this device was suitable to monitor heparin therapy. However, monitoring of RH was not evaluated.Study Objectives. To evaluate in vitro and ex vivo the responsiveness and reproducibility for hirudin monitoring of the whole blood monitor and of plasma APTT assays, which were performed with several reagents and two conventional coagulometers.Results. Large interindividual differences in hirudin responsiveness were noted in both the in vitro and the ex vivo experiments. The relationship between the APTT, expressed as clotting time or ratio of initial and prolonged APTT, and the hirudin concentration was nonlinear. A 1.5-fold increase of the clotting times was obtained at 150-200 ng/ml plasma. However, only a 2-fold increase was obtained at hirudin levels varying from 300 ng to more than 750 ng RH/ml plasma regardless of the assays. The relationship linearized upon logarithmic conversion of the ratio and the hirudin concentration. Disregarding the interindividual differences, and presuming full linearity of the relationship, all combinations were equally responsive to hirudin.Conclusions. All assays were equally responsive to hirudin. Levels up to 300 ng/ml plasma can be reliably estimated with each assay. The manual device may be preferable in situations where rapid availability of test results is necessary.