Clinical, Neuroimaging, and Genetic Markers in Cerebral Amyloid Angiopathy-Related Inflammation: A Systematic Review and Meta-Analysis

Background: There are limited data regarding the prevalence of distinct clinical, neuroimaging and genetic markers among patients diagnosed with cerebral amyloid angiopathy-related inflammation (CAA-ri). We sought to determine the prevalence of clinical, radiological, genetic and cerebrospinal fluid biomarker findings in patients with CAA-ri. Methods: A systematic review and meta-analysis of published studies including patients with CAA-ri was conducted to determine the prevalence of clinical, neuroimaging, genetic and cerebrospinal fluid biomarker findings. Subgroup analyses were performed based on (1) prospective or retrospective study design and (2) CAA-ri diagnosis with or without available biopsy. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using Cochran-Q and I2-statistics. Results: We identified 4 prospective and 17 retrospective cohort studies comprising 378 patients with CAA-ri (mean age, 71.5 years; women, 52%). The pooled prevalence rates were as follows: cognitive decline at presentation 70% ([95% CI, 54%-84%]; I2=82%), focal neurological deficits 55% ([95% CI, 40%-70%]; I2=82%), encephalopathy 54% ([95% CI, 39%-68%]; I2=43%), seizures 37% ([95% CI, 27%-49%]; I2=65%), headache 31% ([95% CI, 22%-42%]; I2=58%), T2/fluid-attenuated inversion recovery-hyperintense white matter lesions 98% ([95% CI, 93%-100%]; I2=44%), lobar cerebral microbleeds 96% ([95% CI, 92%-99%]; I2=25%), gadolinium enhancing lesions 54% ([95% CI, 42%-66%]; I2=62%), cortical superficial siderosis 51% ([95% CI, 34%-68%]; I2=77%) and lobar macrohemorrhage 40% ([95% CI, 11%-73%]; I2=88%). The prevalence rate of the ApoE (Apolipoprotein E) ϵ4/ϵ4 genotype was 34% ([95% CI, 17%-53%]; I2=76%). Subgroup analyses demonstrated no differences in these prevalence rates based on study design and diagnostic strategy. Conclusions: Cognitive decline was the most common clinical feature. Hyperintense T2/fluid-attenuated inversion recovery white matter lesions and lobar cerebral microbleeds were by far the most prevalent neuroimaging findings. Thirty-four percent of patients with CAA-ri have homozygous ApoE ϵ4/ϵ4 genotype and scarce data exist regarding the cerebrospinal fluid biomarkers and its significance in these patients

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Advanced glycation end-products induce endoplasmic reticulum stress in human aortic endothelial cells

Background: Advanced glycation end products (AGEs), the final products of the Maillard reaction, have been shown to impair endothelial proliferation and function, thus contributing to endothelial cell injury present in diabetes, inflammatory and cardiovascular diseases. Endoplasmic reticulum (ER) stress triggered under hyperglycemic, hypoxic and oxidative conditions has been implicated in endothelial dysfunction through activation of the unfolded protein response (UPR). The present study investigates the role of AGEs in ER stress induction in human aortic endothelial cells exposed to variable AGE treatments. Methods: Human aortic endothelial cells (HAEC) were treated with increasing concentrations (100, 200 μg/mL) of AGE-bovine serum albumin (AGE-BSA) at different time-points (24, 48, 72 h). The induction of ER stress and the involved UPR components were investigated on mRNA and protein levels. Apoptosis was quantitatively determined by flow cytometry detecting propidium iodide expression and annexin V binding simultaneously. Results: AGEs administration significantly reduced HAEC proliferation in a time-and dose-dependent manner. An immediate induction of the ER chaperones GRP78, GRP94 and the transcriptional activator, XBP-1 was observed at 24 h and 48 h. A later induction of the phospho-elF2á and proapoptotic transcription factor CHOP was observed at 48 h and 72 h, being correlated with elevated early apoptotic cell numbers at the same time-points. Conclusions: The present study demonstrates that AGEs directly induce ER stress in human aortic endothelial cells, playing an important role in endothelial cell apoptosis. Targeting AGEs signaling pathways in order to alleviate ER stress may prove of therapeutic potential to endothelial dysfunction-related disorders. © 2014 by Walter de Gruyter Berlin Boston

Vaccination and Malaria Prevention among International Travelers Departing from Athens International Airport to African Destinations

Background. International travel to Africa has grown dramatically over the last decade along with an increasing need to understand the health issues for travelers. The current survey aimed to assess vaccination and malaria prevention of travelers visiting Africa. Methods. A questionnaire-based survey was conducted from of November 1, 2011 to of April 30, 2013 at Athens International Airport. Results. A total of 360 travelers were studied; 68% were men. Their mean age was 39.9 years. Previous travel to tropical countries was reported by 71.9% of them. Most frequent destination was sub-Saharan Africa (60%). Most of them traveled for ≥1 month (62%). The main reason for travel was work (39.7%). Only 47% sought pretravel consultation. Hepatitis A, typhoid, and meningococcal vaccines were administered to 49.8%, 28%, and 26.6%, respectively, and malaria chemoprophylaxis to 66.8% of those who visited sub-Saharan Africa. A history of previous travel to a tropical country, elementary level of education, and traveling for visiting friends and relatives, and for short duration were significant determinants for not pursuing pretravel consultation. Conclusions. The current survey revealed important inadequacies in vaccine and malaria prophylaxis of travelers departing to Africa. Educational tools should be developed in order to improve awareness of travelers to risk destinations

The nature, frequency and value of stimulation induced seizures during extraoperative cortical stimulation for functional mapping

Purpose: The aim of this retrospective service evaluation was to determine the nature, frequency and clinical value of seizure occurrence during extraoperative direct cortical stimulation for functional mapping in patients undergoing invasive recordings (icEEG) for epilepsy surgery workup. Methods: We reviewed 145 sequential cases of patients with refractory focal epilepsy who underwent intracranial electrode implantation and extraoperative direct cortical stimulation (CS) for functional mapping. CS intended for mapping can elicit as a by-product electrical or electroclinical events, such as afterdischarges, subclinical EEG seizures, and stimulation-induced seizures (SIS). SIS may have habitual or non-habitual semiology (as defined by comparison to the patient’s spontaneous events). Results: In our cohort, electrical (subclinical EEG seizures) or electroclinical events, (SIS) were recorded in 34.5% (50/145) patients during CS. SIS occurred in 23.4% (34/145) of all patients, of which over half were habitual SIS (SIShab). In most cases the location of contacts eliciting habitual SIS originated from the same location as the spontaneous ictal onset zone in icEEG. Of those with SIS hab undergoing surgery (n = 13), seizure freedom was achieved in 61.5%, and of those with SISNH undergoing surgery (n = 10), 40% became seizure free (ns). Conclusions: Electroclinical SIS occur in about a quarter of CS for functional mapping; SIS are habitual in the majority of cases, and where elicited, SIS in icEEG could be an additional diagnostic tool to localize the seizure onset zone. However, a significant minority of stimulations lead to non-habitual SIS

Sideritis euboea extract lowers total cholesterol but not LDL cholesterol in humans: A randomized controlled trial

Aim:Sideritis euboea is used to prepare a widely consumed beverage. We evaluated the biological activity of S. euboea in healthy human subjects, focusing on serum cardiovascular factors, including lipids, inflammation and glucose homeostasis markers. Patients & methods: In a double-blind study, 54 participants were randomly assigned to consume S. euboea aqueous extract food (n = 27, intervention group) or a placebo food (n = 27, control group) for a 1-month period. A total of 47 participants were included in the final analysis. Serum lipids (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, lipoprotein lipase(a)), Homeostasis Model Assessment and inflammatory markers were determined. Results: Total cholesterol was reduced significantly in the intervention group, while no beneficial effects on other lipid parameters and inflammatory markers were observed. In females, S. euboea significantly ameliorated the Homeostasis Model Assessment index. Conclusion: The consumption of S. euboea induces only a significant total cholesterol lowering effect while it exerts insulin-sensitizing actions in females. Larger studies with a longer intervention period should be performed. © 2013 Future Medicine Ltd

Advanced glycation end products upregulate lysyl oxidase and endothelin-1 in human aortic endothelial cells via parallel activation of ERK1/2-NF-κB and JNK-AP-1 signaling pathways

Endothelial dysfunction involves deregulation of the key extracellular matrix (ECM) enzyme lysyl oxidase (LOX) and the vasoconstrictor protein, endothelin-1 (ET-1), whose gene expression can be modulated by the transcriptional activators nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). Advanced glycation end products (AGEs) present an aggravating factor of endothelial dysfunction which upon engagement to their receptor RAGE induce upregulation of mitogen-activated protein kinases (MAPKs), leading to NF-κB and AP-1 potentiation. We hypothesized that AGEs could induce NF-κΒ- and AP-1-dependent regulation of LOX and ET-1 expression via the AGE/RAGE/MAPK signaling axis. Western blot, real-time qRT-PCR, FACS analysis and electrophoretic mobility-shift assays were employed in human aortic endothelial cells (HAECs) following treatment with AGE-bovine serum albumin (AGE-BSA) to investigate the signaling pathway towards this hypothesis. Furthermore, immunohistochemical analysis of AGEs, RAGE, LOX and ET-1 expression was conducted in aortic endothelium of a rat experimental model exposed to high- or low-AGE content diet. HAECs exposed to AGE-BSA for various time points exhibited upregulation of LOX and ET-1 mRNA levels in a dose- and time-dependent manner. Exposure of HAECs to AGE-BSA also showed specific elevation of phospho(p)-ERK1/2 and p-JNK levels in a dose- and time-dependent fashion. AGE administration significantly increased NF-κΒ- and AP-1-binding activity to both LOX and ET-1 cognate promoter regions. Moreover, LOX and ET-1 overexpression in rat aortic endothelium upon high-AGE content diet confirmed the functional interrelation of these molecules. Our findings demonstrate that AGEs trigger NF-κΒ- and AP-1-mediated upregulation of LOX and ET-1 via the AGE/RAGE/MAPK signaling cascade in human endothelial cells, thus contributing to distorted endothelial homeostasis by impairing endothelial barrier function, altering ECM biomechanical properties and cell proliferation. © 2015 Springer International Publishing

Vaccinations and Malaria Chemoprophylaxis of Adolescents Traveling From Greece to International Destinations A Nine-Year Prospective Study

Background: There are few publications focusing on vaccination and malaria chemoprophylaxis in adolescent travelers. We assessed pretravel vaccinations and malaria chemoprophylaxis of adolescents 12-18 years old traveling from Greece to international destinations. Methods: We prospectively studied 239 adolescents 12-18 years old during 2008-2016. A standard questionnaire was used to collect data. Results: Adolescents sought pretravel services at a mean of 24.1 days before departure. Their main destinations were sub-Saharan Africa (79 adolescents; 33.1%), Latin America (56; 23.5%) and North America (26; 10.9%). Almost half (46.1%) of them planned to stay abroad for at least 3 months. Sixteen (7.4%) adolescents planned to visit friends and relatives. The yellow fever vaccine and the typhoid vaccine were the most frequently administered vaccines (74.1% and 20.5%, respectively), while the hepatitis A vaccine and the tetanus-diphtheria vaccine accounted for most routine vaccinations (18% and 14.2%, respectively). The rabies and the typhoid fever vaccines were administered inadequately to adolescents traveling to endemic areas. Malaria chemoprophylaxis should have been prescribed in many cases traveling to sub-Saharan Africa and the Indian subcontinent. Conclusions: Only a small number of adolescents from Greece traveling abroad seek pretravel counseling. We found significant gaps in typhoid fever and rabies vaccinations of adolescents traveling to endemic areas. We also found gaps in prescription of malaria chemoprophylaxis for those traveling to high-risk areas. There is a need to develop communication strategies to access adolescent travelers and improve appropriate vaccination and use of malaria chemoprophylaxis

Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene

Background: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations occur in 15% of familial isolated pituitary adenoma (FIPA) cases. To date, studies have focused on the identification of such mutations in large international cohorts. Detailed genetic and clinical studies within AIP mutation-positive families have been limited. Aim: To undertake a comprehensive study of a large Brazilian FIPA kindred with an E174 frameshift (E174fs) AIP mutation to assess clinical, hormonal, and radiological features in mutation carriers. Methods: The kindred included 122 subjects across six generations; all underwent clinical examination. Genetic studies were performed to identify E174fs mutation carriers. E174fs-positive subjects underwent magnetic resonance imaging (MRI) and hormonal assessments. Results: Of the ten germline AIP mutation carriers, three had pituitary tumors, while seven were asymptomatic carriers. Three patients with pituitary tumors showed variability in terms of tumor phenotype (two with acromegaly, one with prolactinoma, or mixed prolactin/GH-secreting tumor) and age at diagnosis; both patients with acromegaly had poor responses to octreotide. Tumor AIP immunohistochemistry from the operated patient showed decreased expression when compared with normal tissue. Two adult subjects with normal MRI had elevated IGF-I in the absence of other causes. A 2-year-old child with the E174fs mutation and a normal MRI had premature thelarche, ovarian development, and advanced bone age in the absence of other underlying causes. Conclusions: The penetrance of pituitary tumors in AIP mutation-positive adult subjects was 33.3%, while clinical/hormonal features were variable. The features noted in AIP-mutation carriers in this kindred suggest that clinical characteristics of such carriers may extend beyond pituitary tumors