Can intracranial time-of-flight-MR angiography predict extracranial carotid artery stenosis?

Objectives: Extracranial stenosis of the internal carotid artery (ICA) is an important cause of ischemic stroke and transient ischemic attack (TIA). It can be diagnosed using contrast-enhanced CT or MR angiography (MRA) as well as Doppler ultrasound. In this study, we assessed the diagnostic value of intracranial time-of-flight (TOF) MRA to predict extracranial ICA stenosis (ICAS). Methods: We retrospectively analyzed consecutive patients with acute ischemic stroke or TIA and middle- (50-69%) or high-grade (70-99%) unilateral extracranial ICAS according to NASCET criteria assessed by ultrasound between January 2016 and August 2018. The control group consisted of patients without extracranial ICAS. Intraluminal signal intensities (SI) of the intracranial ICA on the side of the extracranial stenosis were compared to the contralesional side on TOF-MRA source images. SI ratios (SIR) of contralesional:lesional side were compared between groups. Results: In total, 151 patients were included in the main analysis. Contralesional:lesional SIR in the intracranial C4-segment was significantly higher in patients with ipsilateral extracranial ICA stenosis (n = 51, median 74 years, 57% male) compared to the control group (n = 100, median 68 years, 48% male). Mean SIR was 1.463 vs. 1.035 (p < 0.001) for right-sided stenosis and 1.362 vs. 1.000 (p < 0.001) for left-sided stenosis. Receiver-operating characteristic curve demonstrated a cut-off value of 1.086 for right-sided [sensitivity/specificity 75%/81%; area under the curve (AUC) 0.81] and 1.104 for left-sided stenosis (sensitivity/specificity 70%/84%; AUC 0.80) in C4 as a good predictor for high-grade extracranial ICAS. Conclusions: SIR on TOF-MRA can be a marker of extracranial ICAS

Frequency of silent brain infarction in transient global amnesia

Background: and purpose To determine the frequency and distribution pattern of acute DWI lesions outside the hippocampus in patients clinically presenting with Transient Global Amnesia (TGA). Methods: Consecutive patients clinically presenting with TGA between January 2010 and January 2017 admitted to our hospital were retrospectively evaluated. All patients fulfilled diagnostic criteria of TGA. We analyzed imaging and clinical data of all patients undergoing MRI with high-resolution diffusion-weighted imaging within 72 h from symptom onset. Results: A total of 126 cases were included into the study. Fifty-three percent (n = 71/126) presented with one or more acute lesions in hippocampal CA1-area. Additional acute DWI lesions in other cortical regions were found in 11% (n = 14/126). All patients with DWI lesions outside the hippocampus presented with neurological symptoms typical for TGA (without additional symptoms.) Conclusions: In a relevant proportion of clinical TGA patients, MRI reveals acute ischemic cerebral lesions. Therefore, cerebral MRI should be performed in patients with TGA to identify a possible cardiac involvement and to detect stroke chameleons

Whole-Inactivated Influenza Virus Is a Potent Adjuvant for Influenza Peptides Containing CD8+ T Cell Epitopes

Influenza peptide antigens coding for conserved T cell epitopes have the capacity to induce cross-protective influenza-specific immunity. Short peptide antigens used as a vaccine, however, often show poor immunogenicity. In this study, we demonstrate that whole-inactivated influenza virus (WIV) acts as an adjuvant for influenza peptide antigens, as shown by the induction of peptide-specific CD8+ T cells in HLA-A2.1 transgenic mice upon vaccination with the influenza-M1-derived GILGFVFTL peptide (GIL), formulated with WIV. By screening various concentrations of GIL and WIV, we found that both components contributed to the GIL-specific T cell response. Whereas co-localization of the peptide antigen and WIV adjuvant was found to be important, neither physical association between peptide and WIV nor fusogenic activity of WIV were relevant for the adjuvant effect of WIV. We furthermore show that WIV may adjuvate T cell responses to a variety of peptides, using pools of either conserved wild-type influenza peptides or chemically altered peptide ligands. This study shows the potential of WIV as an adjuvant for influenza peptides. The simple formulation process and the solid safety record of WIV make this an attractive adjuvant for T cell peptides, and may also be used for non-influenza antigens

MYD88 mutations identify a molecular subgroup of diffuse large B-cell lymphoma with an unfavorable prognosis

The 2016 World Health Organization classification defines diffuse large B-cell lymphoma (DLBCL) subtypes based on Epstein-Barr virus (EBV) infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis. A subset of DLBCL, however, is characterized by activating mutations in MYD88/CD79B. We investigated whether MYD88/CD79B mutations could improve the classification and prognostication of DLBCL. In 250 primary DLBCL, MYD88/CD79B mutations were identified by allele-specific polymerase chain reaction or next-generationsequencing, MYC/BCL2/BCL6 rearrangements were analyzed by fluorescence in situ hybridization, and EBV was studied by EBV-encoded RNA in situ hybridization. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to the International Prognostic Index (IPI) were investigated. MYD88 and CD79B mutations were identified in 29.6% and 12.3%, MYC, BCL2, and BCL6 rearrangements in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, and MYD88/CD79B mutations established the value of molecular markers for the recognition of biologically distinct DLBCL subtypes. MYD88-mutated DLBCL had a significantly inferior 5-year overall survival than wild-type MYD88 DLBCL (log-rank; P=0.019). DLBCL without any of the studied aberrations had superior overall survival compared to cases carrying .1 aberrancy (log-rank; P=0.010). MYD88 mutations retained their adverse prognostic impact upon adjustment for other genetic and clinical variables by multivariable analysis and improved the prognostic performance of the IPI. This study demonstrates the clinical utility of defining MYD88-mutated DLBCL as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of MYD88 in routine diagnostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies

Triglyceride-rich lipoproteins and their remnants : metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD. [GRAPHICS] .Peer reviewe

Laparoscopic Heller Myotomy Versus Endoscopic Balloon Dilatation for the Treatment of Achalasia A Network Meta-Analysis

Objective: Comparison of short-and long-term effects after laparoscopic Heller myotomy (LHM) and endoscopic balloon dilation (EBD) considering the need for retreatment. Background: Previously published studies have indicated that LHM is the most effective treatment for Achalasia. In contrast to that a recent randomized trial found EBD equivalent to LHM 2 years after initial treatment. Methods: A search in Medline, PubMed, and Cochrane Central Register of Controlled Trials was conducted for prospective studies on interventional achalasia therapy with predefined exclusion criteria. Data on success rates after the initial and repeated treatment were extracted. An adjusted network meta-analysis and meta-regression analysis was used, combined with a headto-head comparison, for follow-up at 12, 24, and 60 months. Results: Sixteen studies including results of 590 LHM and EBD patients were identified. Odds ratio (OR) was 2.20 at 12 months (95% confidence interval: 1.18-4.09; P = 0.01); 5.06 at 24 months (2.61-9.80; P &lt; 0.00001) and 29.83 at 60 months (3.96-224.68; P = 0.001). LHM was also significantly superior for all time points when therapy included re-treatments , and 17.90 (2.17-147.98); P ≤ 0.01 for all comparisons) Complication rates were not significantly different. Meta-regression analysis showed that amount of dilations had a significant impact on treatment effects (P = 0.009). Every dilation (up to 3) improved treatment effect by 11.9% (2.8%-21.8%). Conclusions: In this network meta-analysis, LHM demonstrated superior short-and long-term efficacy and should be considered first-line treatment of esophageal achalasia. Keywords: achalasia, economic cost, endoscopy, esophagus, health, idiopathic achalasia, laparoscopic surgery, meta-analysis, motility disorders, network meta-analysis, review, surgery (Ann Surg 2013;258:943-952 A chalasia is a rare esophageal motility disorder caused by degeneration of the myenteric plexus, resulting in esophageal dysmotility and incomplete lower esophageal sphincter relaxation. The disease is likely caused by a virus-induced autoimmune response, but this is still debated. 1 The incidence in the Western world is 1/100 000. 2-4 Treatment can be pharmacological, endoscopic, or surgical. Pharmacological treatment is only marginally effective and is reserved for patients with mild symptoms or who refuse other treatments. 7-9 Several studies and a large meta-analysis have indicated that laparoscopic Heller myotomy (LHM) is the most effective treatment for achalasia. 3,4,10 However, a recent large prospective randomized controlled trial (RCT) comparing EBD and LHM has challenged this view. 11 This study found similar success rates for EBD and LHM 2 years after initial treatment. However, the number of EBD interventions per patient was notably higher than other studies. 3,11 The purpose of this meta-analysis is to determine which treatment is most effective at relieving symptoms and to further clarify the impact of retreatments for patients with achalasia. METHODS This meta-analysis was registered in the international register of systematic reviews (PROSPERO) (CRD42012002071). 12 Search Strategy and Trial Selection A prospective search of Medline, PubMed, and Cochrane Central Register of Controlled Trials was performed to identify relevant publications. The search keyword was &quot;Esophageal Achalasia.&quot; Subsequently, the search was limited by the terms &quot;Human,&quot; &quot;Clinical Trial,&quot; and publication language &quot;English.&quot; Publications from 1975 through October 2011 were considered for review To obtain indirect evidence by adjusted network meta-analysis, relative evidence is needed (LHM vs X; EBD vs X). Therefore, success rates were compared with those of either EBTI or open Heller myotomy (OHM). Direct evidence was achieved from head-to-hea

Increased Oral Detection, but Decreased Intestinal Signaling for Fats in Mice Lacking Gut Microbiota

Germ-free (GF) mice lacking intestinal microbiota are significantly leaner than normal (NORM) control mice despite consuming more calories. The contribution of microbiota on the recognition and intake of fats is not known. Thus, we investigated the preference for, and acceptance of, fat emulsions in GF and NORM mice, and associated changes in lingual and intestinal fatty acid receptors, intestinal peptide content, and plasma levels of gut peptides. GF and NORM C57Bl/6J mice were given 48-h two-bottle access to water and increasing concentrations of intralipid emulsions. Gene expression of the lingual fatty acid translocase CD36 and protein expression of intestinal satiety peptides and fatty-acid receptors from isolated intestinal epithelial cells were determined. Differences in intestinal enteroendocrine cells along the length of the GI tract were quantified. Circulating plasma satiety peptides reflecting adiposity and biochemical parameters of fat metabolism were also examined. GF mice had an increased preference and intake of intralipid relative to NORM mice. This was associated with increased lingual CD36 (P<0.05) and decreased intestinal expression of fatty acid receptors GPR40 (P<0.0001), GPR41 (P<0.0001), GPR43 (P<0.05), and GPR120 (P<0.0001) and satiety peptides CCK (P<0.0001), PYY (P<0.001), and GLP-1 (P<0.001). GF mice had fewer enteroendocrine cells in the ileum (P<0.05), and more in the colon (P<0.05), relative to NORM controls. Finally, GF mice had lower levels of circulating leptin and ghrelin (P<0.001), and altered plasma lipid metabolic markers indicative of energy deficits. Increased preference and caloric intake from fats in GF mice are associated with increased oral receptors for fats coupled with broad and marked decreases in expression of intestinal satiety peptides and fatty-acid receptors

Predicting the influence of liposomal lipid composition on liposome size, zeta potential and liposome-induced dendritic cell maturation using a design of experiments approach.

In this study, the effect of liposomal lipid composition on the physicochemical characteristics and adjuvanticity of liposomes was investigated. Using a design of experiments (DoE) approach, peptide-containing liposomes containing various lipids (EPC, DOPE, DOTAP and DC-Chol) and peptide concentrations were formulated. Liposome size and zeta potential were determined for each formulation. Moreover, the adjuvanticity of the liposomes was assessed in an in vitro dendritic cell (DC) model, by quantifying the expression of DC maturation markers CD40, CD80, CD83 and CD86. The acquired data of these liposome characteristics were successfully fitted with regression models, and response contour plots were generated for each response factor. These models were applied to predict a lipid composition that resulted in a liposome with a target zeta potential. Subsequently, the expression of the DC maturation factors for this lipid composition was predicted and tested in vitro; the acquired maturation responses corresponded well with the predicted ones. These results show that a DoE approach can be used to screen various lipids and lipid compositions, and to predict their impact on liposome size, charge and adjuvanticity. Using such an approach may accelerate the formulation development of liposomal vaccine adjuvants.Drug Delivery Technolog

Practical Applications as a Source of Credibility: A Comparison of Three Fields of Dutch Academic Chemistry

In many Western science systems, funding structures increasingly stimulate academic research to contribute to practical applications, but at the same time the rise of bibliometric performance assessments have strengthened the pressure on academics to conduct excellent basic research that can be published in scholarly literature. We analyze the interplay between these two developments in a set of three case studies of fields of chemistry in the Netherlands. First, we describe how the conditions under which academic chemists work have changed since 1975. Second, we investigate whether practical applications have become a source of credibility for individual researchers. Indeed, this turns out to be the case in catalysis, where connecting with industrial applications helps in many steps of the credibility cycle. Practical applications yield much less credibility in environmental chemistry, where application-oriented research agendas help to acquire funding, but not to publish prestigious papers or to earn peer recognition. In biochemistry practical applications hardly help in gaining credibility, as this field is still strongly oriented at fundamental questions. The differences between the fields can be explained by the presence or absence of powerful upstream end-users, who can afford to invest in academic research with promising long term benefits