Oxidative stress and DNA damage in white matter lesions of the human ageing brain

White matter lesions (WML), identified as hyperintensities on T2-weighted magnetic resonance images (MRI) in the ageing brain, are associated with dementia and depression in the elderly. Ischaemia may contribute to their pathogenesis but the exact role of glial cell pathology remains unclear. Recent studies have concluded that oxidative stress is present in high levels in the deep subcortical white matter lesions when compared to periventricular white matter lesions. The current study investigates the hypothesis that oxidative DNA damage contributes to the pathogenesis of WML, specifically the deep subcortical WM (DSCL). Oxidative DNA damage was investigated in WML and control WM, both from cases with WML (referred to as lesional controls) and without WML derived from the MRC-Cognitive Function and Ageing Study. Lesions were previously identified using post mortem MRI. 8-hydroxy-2’-deoxyguanosine (8-OHdG) was detected by immunohistochemisty and nuclear expression quantified. Double staining was performed to colocalise 8-OHdG with markers for specific cell type (e.g. CD68 for microglia). Expression of Malonaldehyde (MDA) (marker of lipid peroxidation), gamma histone H2AX (ɣH2AX) and DNA dependent protein kinase (DNA-PK) (markers of DNA damage response) were quantified by Western Blotting. -galactosidase and p16 were used to detect induction of cellar senescence as a downstream effect of persistent DNA damage response. QPCR array was carried out using whole tissue RNA extracts to measure differences in expression of key senescence and DNA damage response genes. Both WML and lesional control WM showed significantly elevated level of DNA oxidation than control WM, whilst WML and lesional controls did not differ. Persistent DNA damage response was detected using MDA, ɣH2AX and DNA-PK antibodies which activated senescence pathways demonstrated in galactosidase activity as well as p16, p21 and p53 as other indicators of cellular senescence. Key genes involved in DNA damage and senescence pathways were highly expressed in CL tissue. Oxidised DNA is up regulated in ageing WM in different levels and may contribute to pathogenesis of WML. The similarity in the level of oxidative DNA damage in lesional control WM and WML suggests that oxidative damage is widespread in WM in cases with lesions indicating that WML are associated with general WM damage. DNA damage potentially activates cellular senescence as well as cell cycle check proteins, particularly in astrocytes, in aged WM and WML

Effect of Maximum Aggregate Size on the Strength of Normal and High Strength Concrete

Aggregates form 60% to 75% of concrete volume and thus influence its mechanical properties. The strength of (normal or high-strength) concrete is affected by the maximum size of a well-graded coarse aggregate. Concrete mixes containing larger coarse aggregate particles need less mixing water than those containing smaller coarse aggregates, In other words, small aggregate particles have more surface area than a large aggregate particle. In this research, about twenty-two mixtures were covered to study the effect of the MSCA, on compressive strength of (normal strength concrete) and Sixteen mixtures to study the effect of the maximum size of coarse aggregate on compressive strength for (high strength concrete). The concrete mixture is completely redesigned according to the maximum size of coarse aggregate needs and maintaining uniform workability for all sizes of coarse aggregate. The American design method was adopted ACI 211.1, for normal concrete. ACI 211-4R, the design method was adopted for high strength concrete. And use the MSCA with dimensions (9.5, 12.5, 19, 25, 37.5, and 50) mm for normal strength concrete and the MSCA (9.5, 12.5, 19, and 25) mm for high strength concrete. The slump was fixed (75-100) mm for normal strength concrete. Slump is fixed to (25-50) mm for high strength concrete before added Superplasticizer high range water reducer (HRWR). With Fineness Modulus (F.M) fixed to 2.8 for both normal concrete and high-strength concrete. According to the results of the tests, the compressive strength increases with the increase in the MSCA, of the normal concrete and also high – strength concrete. And the effect of the MSCA, on the compressive strength of normal concrete, is higher than that of high-strength concrete

Alendronate Use and Risk of Type 2 Diabetes:A Nationwide Danish Nested Case-Control Study

OBJECTIVE: A link has been proposed between glucose homeostasis and bone metabolism. Bisphosphonates are first-line treatment of osteoporosis, and we aimed to investigate whether the risk of developing type 2 diabetes was associated with prior use of alendronate. RESEARCH DESIGN AND METHODS: We conducted a population-based nested case-control study through access to all discharge diagnoses (ICD-10 system) from the National Danish Patient Registry along with all redeemed drug prescriptions (ATC classification system) from the Health Service Prescription Registry. All cases with a diagnosis of type 2 diabetes between 2008 and 2018 were matched on sex and age with 3 randomly selected controls by incidence-density sampling. Exposure was defined as ever use of alendronate and further grouped as effective and compliant use. ORs were calculated by conditional logistic regression analysis with adjustment for several confounders and test for trend for dose-response relationship. RESULTS: We included 163,588 patients with type 2 diabetes and 490,764 matched control subjects with a mean age of 67 years and 55% male subjects. The odds of developing type 2 diabetes were lower among ever users of alendronate (multiple adjusted OR: 0.64 [95% CI 0.62-0.66]). A test for trend suggested a dose-response relationship between longer effective use of alendronate and lower risk of type 2 diabetes. CONCLUSION: These results suggest a possible protective effect of alendronate in a dose-dependent manner against development of type 2 diabetes

The quality of image encryption techniques by reasoned logic

One form of data is digital images, because of their widespread of frequent exchange over the internet it is necessary to preserve the security and privacy of the images transmitted.There are many image encryption techniques that have different security levels and there are many standards and protocols fortesting the quality of encryption security. The cipher images can be evaluated using various quality measuring criteria, these measures quantify certain features of the image. If there are many methods that can be applied to secure images; the question is what is the most powerful scheme that can be use damong these methods? This research try to answer this question by taking three different encryption methods (rivest cipher 5 (RC5), chaotic and permutation) and measure their quality using the peek signal to noise ratio (PSNR),correlation, entropy, number of pixels changes rate (NPCR) and unified average changing intensity (UACI), the results of these criteria were input to a fuzzy logic system that was used to find the best one among them

The Efficacy of Alendronate Versus Denosumab on Major Osteoporotic Fracture Risk in Elderly Patients With Diabetes Mellitus:A Danish Retrospective Cohort Study

OBJECTIVE: Patients with diabetes mellitus have an increased risk of fractures; however, the underlying mechanism is largely unknown. We aimed to investigate whether the risk of major osteoporotic fractures in diabetes patients differs between subjects initiated with alendronate and denosumab, respectively. METHODS AND RESEARCH DESIGN: We conducted a retrospective nationwide cohort study through access to all discharge diagnoses (ICD-10 system) from the National Danish Patient Registry along with all redeemed drug prescriptions (ATC classification system) from the Health Service Prescription Registry. We identified all subjects with a diabetes diagnosis between 2000 and 2018 and collected data on the first new prescription of anti-osteoporotic treatment between 2011 and 2018. Exposure was defined as either alendronate or denosumab treatment initiated after diabetes diagnosis. Outcome information was collected by identification of all major osteoporotic fracture (MOF) diagnoses, i.e., hip, spine, forearm, and humerus, from exposure until 2018 or censoring by emigration or death. The risk of fracture was calculated as hazard ratios (HR) using multiply adjusted Cox proportional models with death as a competing risk. RESULTS: We included 8,745 subjects initiated with either alendronate (n = 8,255) or denosumab (n = 490). The cohort consisted of subjects with a mean age of 73.62 (SD ± 9.27) years, primarily females (69%) and suffering mainly from type 2 diabetes (98.22%) with a median diabetes duration at baseline of 5.45 years (IQR 2.41–9.19). Those in the denosumab group were older (mean 75.60 [SD ± 9.72] versus 73.51 [SD ± 9.23] years), had a higher proportion of women (81% versus 68%, RR 1.18 [95% CI 1.13–1.24], and were more comorbid (mean CCI 2.68 [95% CI 2.47–2.88] versus 1.98 [95% CI 1.93–2.02]) compared to alendronate initiators. In addition, denosumab users had a higher prevalence of previous fractures (64% versus 46%, RR 1.38 [95% CI 1.28–1.48]). The adjusted HR for any MOF after treatment initiation with denosumab was 0.89 (95% CI 0.78–1.02) compared to initiation with alendronate. CONCLUSION: The risk of incident MOF among subjects with diabetes was similar between those initially treated with alendronate and denosumab. These findings indicate that the two treatment strategies are equally effective in preventing osteoporotic fractures in subjects with diabetes

QR code based two-factor authentication to verify paper-based documents

Important paper-based documents Exposed to forgery such as: official certificates, birth, marriage, death certificates, selling and buying documents and other legal documents is more and more serious and sophisticated. With the purposes of fraud, appropriation of property, job application and assignment in order to swindle public authorities, this forgery has led to material loss, belief deterioration as well as social instability. There are many techniques has been proposed to overcome this issues such as: ink stamps, live signatures, documented the transaction in third party like the court or notary. In this paper, it’s proposed a feasible solution for forgery prevention for paper-based documents using cloud computing application. With the application of Quick Response bidirectional barcode and the usage of hash algorithm. The study aims at developing an electronic verification system for official and issued books (documents, endorsements, and other official books) to/from different sections of the Institute using QR technology

18Fluorodeoxyglucose Accumulation in Arterial Tissues Determined by PET Signal Analysis

BACKGROUND: Arterial 18fluorodeoxyglucose (FDG) positron emission tomography (PET) is considered a measure of atherosclerotic plaque macrophages and is used for quantification of disease activity in clinical trials, but the distribution profile of FDG across macrophages and other arterial cells has not been fully clarified. OBJECTIVES: The purpose of this study was to analyze FDG uptake in different arterial tissues and their contribution to PET signal in normal and atherosclerotic arteries. METHODS: Wild-type and D374Y-PCSK9 transgenic Yucatan minipigs were fed a high-fat, high-cholesterol diet to induce atherosclerosis and subjected to a clinical FDG-PET and computed tomography scan protocol. Volumes of arterial media, intima/lesion, macrophage-rich, and hypoxic tissues were measured in serial histological sections. Distributions of FDG in macrophages and other arterial tissues were quantified using modeling of the in vivo PET signal. In separate transgenic minipigs, the intra-arterial localization of FDG was determined directly by autoradiography. RESULTS: Arterial FDG-PET signal appearance and intensity were similar to human imaging. The modeling approach showed high accuracy in describing the FDG-PET signal and revealed comparable FDG accumulation in macrophages and other arterial tissues, including medial smooth muscle cells. These findings were verified directly by autoradiography of normal and atherosclerotic arteries. CONCLUSIONS: FDG is taken up comparably in macrophage-rich and -poor arterial tissues in minipigs. This offers a mechanistic explanation to a growing number of observations in clinical imaging studies that have been difficult to reconcile with macrophage-selective FDG uptake.This study was supported by the Danish Council for Independent Research/Medical Sciences, Lundbeck Foundation, Danish Heart Foundation, and Aarhus University Research Foundation (AU IDEAS). The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation; and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Dr. Bentzon has served as a consultant for Novo Nordisk A/S; and has within the last 5 years received an investigator-initiated preclinical research grant from Regeneron PharmaceuticalsS

SGLT2 inhibitor treatment is not associated with an increased risk of osteoporotic fractures when compared to GLP-1 receptor agonists:A nationwide cohort study

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased fracture risk. It is debated whether sodium-glucose cotransporter 2 (SGLT2) inhibitors influence fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) with SGLT2 inhibitors compared to glucagon-like peptide 1 (GLP-1) receptor agonists when used as add-on therapies to metformin. METHODS: We conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either SGLT2 inhibitors or GLP-1 receptor agonists were identified and enrolled from 2012 to 2018. Subjects were then propensity-score matched 1:1 based on age, sex, and index date. Major osteoporotic fractures (MOF) were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. RESULTS: In total, 27,543 individuals treated with either combination were identified and included. After matching, 18,390 individuals were included in the main analysis (9,190 in each group). Median follow-up times were 355 [interquartile range (IQR) 126-780] and 372 [IQR 136-766] days in the SGLT2 inhibitor and GLP-1 receptor agonist group, respectively. We found a crude HR of 0.77 [95% CI 0.56-1.04] for MOF with SGLT2 inhibitors compared to GLP-1 receptor agonists. In the fully adjusted model, we obtained an unaltered HR of 0.77 [95% CI 0.56-1.05]. Results were similar across subgroup- and sensitivity analyses. CONCLUSION: These results suggest that SGLT2 inhibitors have no effect on fracture risk when compared to GLP-1 receptor agonists. This is in line with results from previous studies

The risk of major osteoporotic fractures with GLP-1 receptor agonists when compared to DPP-4 inhibitors:A Danish nationwide cohort study

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin. METHODS: We conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen’s Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects. RESULTS: In total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76–1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73–1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49–0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis. CONCLUSION: In our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture