Understanding the Contributions of Alzheimer’s Disease & Cardiovascular Risks to Cerebral Small Vessel Disease Manifest as White Matter Hyperintensities on Magnetic Resonance Imaging (MRI)

Introduction: Alzheimer’s Diseases (AD) & cerebral small vessel disease associated with cardiovascular risk factors (cSVD) frequently coexist, differentially affecting both imaging and clinical features associated with aging and dementia. We hypothesized that Magnetic Resonance Imaging (MRI) can be used in novel ways to identify relative contributions of AD & cardiovascular risks to cSVD and brain atrophy, generating new biomarkers & insights into mixed disease states associated with cognitive decline and dementia. Methods: Three experiments were conducted to address the overarching hypothesis. First, we visually rated the clinical MRI of 325 participants from a community-based cross-sectional sample to elucidate the relative association of age, AD (visualized as hippocampal atrophy) and cSVD (visualized as white matter hyperintensities; WMH) with global brain atrophy in experiment 1. In experiment 2, we analyzed cross-sectional MRI scans from 62 participants from the University of Kentucky Alzheimer’s Disease Center (UKADC) with available clinical data on cardiovascular risk and cerebrospinal fluid (CSF) beta-amyloid levels as a marker of AD. Voxel wise regression was used to examine the association of white matter hyperintensities with AD and/or cardiovascular risk (hypertension). Experiment 3, examined longitudinal MRI changes in WMH volumes in 377 participants from the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI 2). Subjects were categorized into three groups based on WMH volume change, including those that demonstrated regression (n=96; 25.5%), stability (n=72; 19.1%), and progression (n=209; 55.4%) of WMH volume over time. Differences in brain atrophy measures and cognitive testing among the three group were conducted. Results: In the first experiment, logistic regression analysis demonstrated that a 1-year increase in age was associated with global brain atrophy (OR = 1.04; p = .04), medial temporal lobe atrophy (MTA; a surrogate of AD) (OR = 3.7; p \u3c .001), and WMH as surrogate of cSVD (OR = 8.80; p \u3c .001). Both MTA and WMH were strongly associated with global brain atrophy in our study population, with WMH showing the strongest relationship after adjusting for age. In the second experiment, linear regression as well as mediation and moderation analyses demonstrated significant main effects of hypertension (HTN; the strongest risk factor associated with cSVD) and CSF Aβ 1-42 (a surrogate of AD) on WMH volume, but no significant HTN×CSF Aβ 1-42 interaction. Further exploration of the independence of HTN and Aβ using a voxelwise analysis approach, demonstrated unique patterns of WM alteration associated with either hypertension or CSF Aβ 1-42, confirming that both independently contribute to WMH previously classified as cSVD. Extending this work into a longitudinal model rather than focusing on purely cross-sectional associations, we demonstrated that spontaneous WMH regression is common, and that such regression is associated with a reduced rate of global brain atrophy (p = 0.012), and improvement in memory function over time (p = 0.003). Conclusion: These data demonstrate that both AD and cSVD frequently coexist in the same brain, contributing differentially to alterations in brain structure, subcortical white matter injury, and cognitive function. These effects can be disentangled using MRI, and while we currently lack therapeutic interventions to halt or reverse AD, the dynamic WMH change evident in our data clearly suggests that the ability to reverse cSVD exists today

CEREBROVASCULAR RISK FACTORS, ARTERIOLAR SCLEROSIS, AND COGNITIVE DECLINE IN THE KENTUCKY APPALACHIAN “STROKE-BELT”

The relationship between cerebrovascular disease (CVD) risk factors and cognitive impairment or dementia has been widely studied with significant variability in findings between groups. We hypothesized that chronic small vessel injury in the form of arteriolar sclerosis, measured quantitatively using MRI to measure total white matter hyperintensity (WMH) volumes, would identify specific association of CVD risk factors and patterns of cognitive decline, associated with mild cognitive impairment of the cerebrovascular type, that represent the core features of vascular cognitive impairment in our cohort. A Cross-sectional analysis of clinical and quantitative MRI data on 114 subjects with normal cognitive function (n=52) and mild cognitive impairment (MCI; n=62) was performed. Quantitative total WMH volumes were examined in relation to potentially causative CVD risk factors and resultant test scores across cognitive domains using linear regression models adjusted for age, gender, and education. Among CVD risk factors analyzed, age (p\u3c 0.001), education (p= 0.003), hypertension (p= 0.012), and hyperlipidemia (p= 0.008) demonstrated the strongest associations with WMH volumes. Conversely, diabetes, smoking, history of heart attacks, atrial fibrillation, and history of stroke that have shown associations with CVD pathology on imaging in other studies were not statistically associated with increased WMH in this cohort. WMH volumes were associated with decrease performance on the Trial Making Test type A & B and long delayed free recall on the California Verbal Learning Test. Our findings suggest similarities and yet differences in comparison to other studies. Hypertension and hyperlipidemia appear to represent common shared risks across geographically disparate groups. Our findings, like others, suggest CVD pathology impact processing speed and executive function and provide further evidence for CVD effects on short-term memory in those at risk for cognitive decline and the future development of dementia in our cohort

Implementation of ACR and AVR controls for high voltage gain DC-DC Converter

Step up power conversion is universally used in many applications. The application that uses step-up power conversion can be observed in renewable energy such as photovoltaic (PV) system, wind turbine, data center and Electric vehicle. There are many applications which use the DC-DC boost converter to get higher DC voltage from the low input voltage. In this project, Marx topology boost converter (MTBC) analyzed and proposed for conversion from low input dc voltage to high output dc voltage. (MTBC) depends on the principle of the Marx generator. The proposed (MTBC) is multi-stage and consist from 4-stage, by multistage of converter the stress in the components will be reduced, where the parallel charging at input side to reduce the current stress, and series discharging at output to reduce the voltage stress. The stress on the components of the converter will inversely proportional with a number of stages. By implementation of ACR and AVR combination with using PI control technique the output voltage can be controlled. Based on the simulation results the obtained output voltage 400V DC by boosting input voltage 48V DC and by using 4- stage proposed converter, but any drop in the value of input voltage will effect on the output voltage, so that when battery voltage drop to 40V the output will be 340V. After implementing the control system for the AVR and ACR and combine between them, it will be possible to obtain 400V from different value input voltage (40V, 45V, 55V), as well as for 450V and 500V output voltage

Die Untersuchung und Charakterisierung von Biomarkern im Nierenzell- und Prostatakarzinom

Renal cell carcinoma and prostate carcinoma are two of the most common urologic malignancies. There are several factors like hereditary, sporadic and environmental factors, which play an important role in the development of these tumors. Both tumers are usually discovered by routine examination or after appearance of symptoms in advanced tumor stages. The aim of this work was to study biological markers in prostate cancer and renal cell carcinomas. We investigated in renal cell carcinoma the mRNA expression of PIWI (P- element induced wimpy testis) like genes (PIWIL 1 – 4), which belong to the Argonaute gene family. Piwil 1 – 4 proteins play in eukaryotes an important role in spermatogenesis, self-renewal of stem cells, chromatin remodeling, transposon, and RNA silencing. The mRNA expression of PIWIL 1 – 4 genes was analyzed by qPCR in tumor and corresponding normal tissue of 73 clear cell renal cell carcinoma patients. The mRNA expression levels of PIWIL 1, 2 and 4 are significantly correlated with each other both in the tumor and normal tissue. The PIWIL 4 mRNA expression is significantly higher in the tumor compared to normal tissue. PIWIL 1 mRNA expression in the tumor differs significantly with the age of diagnosis, i.e., it is higher at younger age of diagnosis. In corresponding normal tissue the PIWIL 1 mRNA expression differs significantly with the location of the organ (left-right polarity). The expression of uPA system members was investigated in prostate carcinoma. The uPA system consists of the urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR) and two plasminogen activator inhibitors (PAI-1 and PAI -2). These uPA system components play an important role in the degradation of extracellular matrix, angiogenesis, cell growth, -migration, -adhesion, -proliferation, and survival of cells in various tumors. The mRNA expression in the tissue and protein expression in the serum of the uPA system components were investigated in different cohorts of prostate cancer patients. Statistical analysis showed several correlations for the uPA system members with each other and with the clinical and survival data. The mRNA expression of uPA, PAI-1 and uPAR correlated significantly with each other. The mRNA expression of uPA associates with the Gleason Score. Elevated uPAR protein level in serum correlated with poor prognosis of prostate cancer patients. We found in silico the microRNA miR-143 as a regulator for uPAR. We confirmed for the first time by luciferase assay the regulation of uPAR expression by miR-143. After the binding of miR-143 to uPAR 3`UTR a reduction in the luciferase activity could be detected. Similarly, we could find after transfection with pre-mir-143 a reduction of endogenous uPAR protein expression by western blot. The miR-143 expression was characterized by RT qPCR in PCa tissue of two patient cohorts. We found a significant reduction in the expression of miR-143 in the tumor tissues in comparison to corresponding normal tissues. In addition, the functional effect of miR-143 modulation was examined on the growth, proliferation, migration and cell cycle in the prostate cancer cell lines DU-145, PC-3 and LNCaP respectively, cytotoxicity increased in DU-145 cells after transfection with pre-miR-143, moreover the viability and proliferation increased in PC-3 cells after transfection with anti-miR-143. In the LNCaP cell line we detected no significant changes after the modulation of miR-143 expression. In summary, our results showed significant correlations between the expression of uPA system members as well as PIWI-like genes and several clinical factors and / or the survival data. This means that the studied parameters could be potentially used in combination with other molecular factors as diagnostic or prognostic biomarkers for prostate cancer or renal cell carcinomas.Nierenzell- und Prostatakarzinom sind zwei der am häufigsten vorkommenden, urologischen, bösartigen Tumoren. Bei der Entstehung von diesen Tumoren spielen hereditäre, sporadische und umweltbedingte Faktoren eine Rolle. Beide Tumoren werden meistens durch Routine-Untersuchungen oder nach Auftreten von Symptomen in vorgeschrittenen Tumorstadien entdeckt. Ziel dieser Arbeit war die Untersuchung von biologischen Markern in Prostata- und Nierenzellkarzinomen. Im Nierenzellkarzinom wurde die mRNA-Expression von PIWI (P-element induced wimpy testis) like Genen (PIWIL 1 – 4) untersucht. Die Piwi-like Gene gehören zur Argonauten-Genfamilie. Piwil 1 – 4 Proteine können bei der Spermatogenese, Selbsterneuerung von Stammzellen, Chromatin-Remodelierung, Transposon- und RNA silencing in Eukaryoten eine wichtige Rolle spielen. Die mRNA-Expressionen von PIWIL 1 – 4 Genen in Tumor- und korrespondierendem Normalgewebe von 73 klarzelligen Nierenzellkarzinom-Patienten wurden mittels qPCR untersucht. Die mRNA-Expression der PIWIL 1, 2 und 4 Gene korrelieren miteinander signifikant im Tumor- und Normalgewebe. Die PIWIL 4 mRNA-Expression ist im Tumor signifikant höher im Vergleich zum Normalgewebe. Die PIWIL 1 mRNA-Expression im Tumor unterscheidet sich signifikant mit dem Diagnosealter d.h. ist höher bei jüngerem Diagnosealter. In korrespondierendem Normalgewebe unterscheidet sich die PIWIL 1 mRNA-Expression signifikant mit der Lokalisation des Organs (Links-Rechts-Polarität). Im Prostatakarzinom wurde die Expression von uPA-Systemmitgliedern untersucht. Das uPA-System besteht aus dem Urokinase Plasminogen-Aktivator (uPA), Urokinase Plasminogen-Aktivator Rezeptor (uPAR) und zwei Plasminogen Aktivator Inhibitoren (PAI-1 und PAI-2). Diese uPA-System Komponenten spielen für die Degradation von extrazellulärer Matrix, Angiogenese, Zellwachstum, migration, -adhäsion, -proliferation und das Überleben von Zellen in verschiedenen Tumoren eine wichtige Rolle. Die mRNA-Expression im Gewebe und die Proteinexpression im Serum von uPA- System-Komponenten wurden in verschiedenen PCa-Patienten Kollektiven untersucht. Die statistische Analyse zeigte mehrere Korrelationen für die uPA-Systemmitglieder miteinander und mit den klinischen bzw. Überlebensdaten. Die mRNA-Expression von uPA, PAI-1 und uPAR korrelieren miteinander signifikant. Die mRNA-Expression von uPA ist mit dem Gleason Score assoziiert. Erhöhtes uPAR Protein im Serum korreliert mit einer schlechten Prognose der PCa-Patienten. In silico fanden wir die microRNA miR-143 als Regulator für uPAR. Wir bestätigten mit dem Luziferase Assay erstmalig die Regulation der uPAR-Expression durch die miR-143. Durch die Bindung von miR-143 an die uPAR 3`UTR konnte eine Reduktion in der Luziferaseaktivität nachgewiesen werden. Analog dazu konnte nach der Transfektion mit pre-miR-143 eine Reduktion der endogenen-uPAR Proteinexpression im Western Blot nachgewiesen werden. Die Expression von miR-143 wurde im PCa-Gewebe in zwei Patientenkollektiven mittels RT qPCR untersucht und charakterisiert. Wir fanden eine signifikante Reduktion in der miR-143 Expression im Tumor im Vergleich zu korrespondierendem Normalgewebe. Darüber hinaus wurde die funktionelle Auswirkung der miR 143 Modulation auf das Wachstum, Proliferation, Migration und Zellzyklus in den Prostatakarzinom-Zelllinien DU-145, PC-3 und LNCaP analysiert. Die Zytotoxizität steigt in DU-145 Zellen nach der Transfektion von pre-miR-143, ebenfalls steigen die Viabilität bzw. die Proliferation in PC-3 Zellen nach der Transfektion von Anti-miR-143. Für die Zelllinie LNCaP wurden keine signifikanten Veränderungen nach der Modulation der miR 143 Expression festgestellt. Zusammengefasst zeigten unsere Ergebnisse signifikante Korrelationen zwischen der Expression von uPA-Systemmitgliedern bzw. PIWI-like Genen und mehreren klinischen Faktoren und/oder den Überlebensdaten. Das bedeutet, die untersuchten Parameter könnten potenziell zusammen mit weiteren molekularen Faktoren als diagnostisch oder prognostisch wertvolle Biomarker für Prostata- bzw. Nierenzellkarzinome genutzt werden

Domain-independent Bayesian Model For Aspect Category Detection And Distributed Vector For Implicit Aspect Extraction

The development of Web 2.0 has improved peoples’ ability to share their sentiments, or opinions, on various services or products easily. This is to investigate the public opinions that are expressed within the reviews. Aspect-based sentiment analysis (ABSA) deemed to receive a set of texts (e.g., product reviews or online reviews) and identify the opinion-target (aspect) within each review. Contemporary aspect-based sentiment analysis systems, like the aspect grouping, rely predominantly on lexicon-based and manually labelled seeds that is being incorporated into the topic models. The previously developed systems for Aspect Category Detection (ACD) rely mostly on supervised machine learning techniques. The problem of implicit aspect extraction is being addressed using either pre-constructed rules or pre-labelled clues for performing implicit aspect detection. To cope with these issues, Bayesian probabilistic models proposed to perform the aspect grouping, ACD, and distributed vectors for implicit aspect extraction. Parametric and non-parametric Bayesian models are developed to conduct both the annotated and non-annotated data, that are; Topic-seeds Latent Dirichlet allocation (TSLDA) and Hierarchical Dirichlet Process-Collapsed Gibbs Sampling (HDP-CGS), respectively. The yielded aspect groups using the developed Bayesian models fed into the advised distributed vector (i.e., Skip-gram) for implicit aspect extraction. The proposed methodology evaluated using several online reviews benchmark datasets (including datasets annotated using reviews retrieved from Amazon.com and TripAdvisor.com)

Design of Mobile Healthcare Reminder for Chronic Diabetes

Mobile technology has been increasingly used in healthcare services. However, little has been done in handling patients of chronic disease. Accordingly, this study aims to design a mobile reminder system that cares for patients’ selfmanagement of their chronic diabetes. To achieve the main aim, the following sub objectives have been formulated; (i) to identify the requirements for the mobile healthcare reminder suitable for chronic diabetes, (ii) to develop and construct the prototype of the system, (iii) to evaluate the prototype in terms of perceived usefulness, perceived ease of use, and satisfaction. The prototype has been evaluated using an adapted questionnaire, involving 30 patients in Baghdad Hospital. The results reveal that the prototype is perceived useful and easy to use by the participants. Also, they are highly satisfied with the prototype. The outcome of this study would help mobile healthcare applications developers to design future mobile reminder system particularly for patients who are suffering from chronic diseas

PREDICTORS OF HYPOXEMIA IN BRONCHIOLITIS IN A SAMPLE OF IRAQI INFANTS

Background: Bronchiolitis is the first episode of wheezing associated with low grade fever, rhinitis, tachypnea, and increasing respiratory effort in a previously healthy infant during the winter months, and it is the most common lower respiratory tract infection in infancy. Objectives: This study is designed to analyze the clinical signs and symptoms alone or as combinations as possible predictors of severe hypoxemia in infants with bronchiolitis. Patients and methods: This is a prospective study, which was carried out on 96 infants with a mean age of 7.74 ±3.72 months who were admitted to Children Welfare Teaching Hospital in Medical City-Baghdad with bronchiolitis during the period from 1st October 2006 to the 15th March 2007. They are divided into two groups: group one 46 cases (oxygen saturation (SaO2<90) and group two, 50 cases (SaO2≥90).Complete history taken from care taker and full examination done for each patient. A portable oximeter was used to measure oxygen saturation. Results: Forty nine (51%) of patients were males and 47 were females (49%), with male to female ratio of 1.04:1. The mean age was (7.745±3.7) months. The mean oxygen saturation was (90%), with a median of (84.7%) and a range of (76%-89%) in group one (SaO2<90), while it was (95.32%) with a range of (90%-99%) in group two (SaO2≥90). Conclusions: Reduced ability to feed, sleep disturbances, hypotonia and clinical signs as suprasternal retractions, continuous nasal flaring, tachypnea, grunting, head nodding and cyanosis appeared to be statistically highly significant in this study as predictors of severe hypoxemia. Combinations of signs and symptoms that showed statistically significant association with severe hypoxemia were: grunting or head nodding, cyanosis or head nodding, tachypnea or sleep disturbance, tachypnea or suprasternal retractions, and tachypnea or head nodding (p.value <0.0001) for all mentioned combinations, So we recommend to use these combinations of signs and symptoms as significant predictors of severe hypoxemia especially when pulse oximetry is not available

Design of mobile healthcare reminder for chronic diabetes

Mobile technology has been increasingly used in healthcare services.However, little has been done in handling patients of chronic disease. Accordingly, this study aims to design a mobile reminder system that cares for patients’ self management of their chronic diabetes. To achieve the main aim, the following sub objectives have been formulated; (i) to identify the requirements for the mobile healthcare reminder suitable for chronic diabetes, (ii) to develop and construct the prototype of the system, (iii) to evaluate the prototype in terms of perceived usefulness, perceived ease of use, and satisfaction. The prototype has been evaluated using an adapted questionnaire, involving 30 patients in Baghdad Hospital.The results reveal that the prototype is perceived useful and easy to use by the participants.Also, they are highly satisfied with the prototype. The outcome of this study would help mobile healthcare applications developers to design future mobile reminder system particularly for patients who are suffering from chronic disease

Endothelial‐derived plasma exosome proteins in Alzheimer’s disease angiopathy

Small cerebral vascular disease (SCeVD) demonstrated by white matter hyperintensity (WMH) on MRI contributes to the development of dementia in Alzheimer's disease (AD), but it has not been possible to correlate onset, severity, or protein components of SCeVD with characteristics of WMH in living patients. Plasma endothelial-derived exosomes (EDEs) were enriched by two-step immunoabsorption from four groups of participants with no clinical evidence of cerebrovascular disease: cognitively normal (CN) without WMH (CN without SCeVD, n&nbsp;=&nbsp;20), CN with SCeVD (n&nbsp;=&nbsp;22), preclinical AD (pAD)&nbsp;+&nbsp;mild cognitive impairment (MCI) without SCeVD (pAD/MCI without SCeVD, n&nbsp;=&nbsp;22), and pAD/MCI with SCeVD (n&nbsp;=&nbsp;16) for ELISA quantification of cargo proteins. Exosome marker CD81-normalized EDE levels of the cerebrovascular-selective biomarkers large neutral amino acid transporter 1 (LAT-1), glucose transporter type 1 (Glut-1), and permeability-glycoprotein (p-GP, ABCB1) were similarly significantly higher in the CN with SCeVD and pAD/MCI with SCeVD groups than their corresponding control groups without SCeVD. CD81-normalized EDE levels of Aβ40 and Aβ42 were significantly higher in the pAD/MCI with SCeVD group but not in the CN with SCeVD group relative to controls without SCeVD. Levels of normal cellular prion protein (PrPc), a receptor for amyloid peptides, and phospho-181T-tau were higher in both CN and pAD/MCI with SCeVD groups than in the corresponding controls. High EDE levels of Aβ40, Aβ42, and phospho-181T-tau in patients with WMH suggesting SCeVD appear at the pre-clinical or MCI stage of AD and therapeutic lowering of neurotoxic peptide levels may delay&nbsp;progression of AD&nbsp;angiopathy

White Matter Hyperintensity Regression: Comparison of Brain Atrophy and Cognitive Profiles with Progression and Stable Groups

Subcortical white matter hyperintensities (WMHs) in the aging population frequently represent vascular injury that may lead to cognitive impairment. WMH progression is well described, but the factors underlying WMH regression remain poorly understood. A sample of 351 participants from the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI2) was explored who had WMH volumetric quantification, structural brain measures, and cognitive measures (memory and executive function) at baseline and after approximately 2 years. Selected participants were categorized into three groups based on WMH change over time, including those that demonstrated regression (n = 96; 25.5%), stability (n = 72; 19.1%), and progression (n = 209; 55.4%). There were no significant differences in age, education, sex, or cognitive status between groups. Analysis of variance demonstrated significant differences in atrophy between the progression and both regression (p = 0.004) and stable groups (p = 0.012). Memory assessments improved over time in the regression and stable groups but declined in the progression group (p = 0.003; p = 0.018). WMH regression is associated with decreased brain atrophy and improvement in memory performance over two years compared to those with WMH progression, in whom memory and brain atrophy worsened. These data suggest that WMHs are dynamic and associated with changes in atrophy and cognition